Biphenyl Dimethyl Dicarboxylate Research Articles

Ursodeoxycholic acid in hepatobiliary diseases

Background: This study aimed to summarize evidence of ursodeoxycholic acid (UDCA) use in the management of hepatobiliary diseases, present indications for UDCA use in Korea, and reimbursement criteria for UDCA use in the country.Current Concepts: UDCA is currently approved for the treatment and prevention of gallstone in obese patients with rapid weight loss after post-bariatric surgery, primary biliary cirrhosis (PBC), chronic liver disease with markedly elevated liver function test values, and chronic hepatitis C. However, the approval and reimbursement criteria for UDCA depend on the dose, specific diseases, and circumstances. UDCA is administered at doses of 100, 200, and 300 mg. The 100 mg dose is available over-the-counter, whereas a prescription is required for the 200 and 300 mg doses. The approval standards differed by dose: UDCA 100 mg for biliary diseases and chronic liver disease; UDCA 200 mg for gallstone, PBC, and chronic hepatitis C; and UDCA 300 mg for PBC, gallstone prevention in obese patients, and patients who had undergone gastrectomy. Co-administration of UDCA with antiviral drugs may require patients to bear some costs. UDCA can be combined with either milk thistle or biphenyl dimethyl dicarboxylate but not both.Discussion and Conclusion: UDCA is a relatively safe medication with many benefits. The current reimbursement standards for hepatobiliary diseases include chronic liver disease with elevated liver enzyme levels, gallstone, PBC, chronic hepatitis B, and chronic hepatitis C. Because UDCA is administered at varied doses, it is important to know the appropriate dose and regimen for each condition.

Impact of l-Carnitine Supplementation on Liver Enzyme Normalization in Patients with Chronic Liver Disease: A Meta-Analysis of Randomized Trials.

The effectiveness of l-carnitine in chronic liver disease remains controversial. We conducted this meta-analysis to assess the efficacy of various forms of l-carnitine in the treatment of chronic liver disease. Methods: We searched the Cochrane Library, EMBASE, KMBASE, and Medline databases for all relevant studies published until April 2022 that examined the ability of l-carnitine or its derivatives to normalize liver enzymes in patients with chronic liver disease. We performed meta-analyses of the proportion of patients with alanine aminotransferase (ALT) normalization and post-treatment serum aspartate aminotransferase (AST) and ALT levels. A random effects model was used for meta-analyses. Results: Fourteen randomized controlled trials (1217 patients) were included in this meta-analysis. The proportion of patients in whom ALT normalized was higher in the carnitine-orotate treatment group than in the control group (pooled odds ratio (OR), 95% confidence interval (CI) = 4.61 (1.48–14.39)). The proportion of patients in whom ALT normalized was also higher among those who received the carnitine-orotate complex, a combination of carnitine-orotate, biphenyl dimethyl dicarboxylate, and other minor supplementary compounds than in those who did not without significant heterogeneity (pooled OR (95% CI) = 18.88 (7.70–46.27); df = 1; p = 0.51; I2 = 0%). l-carnitine supplementation effectively lowered serum ALT levels compared to controls (pooled mean difference (95% CI) = −11.99 (−22.48 to −1.49)). Conclusions: l-carnitine supplementation significantly lowered ALT and AST levels and normalized ALT levels in patients with chronic liver disease.

Comparison on the Efficacy and Safety of Biphenyl Dimethyl Dicarboxylate and Ursodeoxycholic Acid in Patients with Abnormal Alanine Aminotransferase: Multicenter, Double-blinded, Randomized, Active-controlled Clinical Trial

Sae Hwan Lee, Gab Jin Cheon, Hong Soo Kim, Young Don Kim, Sang Gyune Kim, Young Seok Kim, Soung Won Jeong, Jae Young Jang and Boo Sung Kim. Korean J Gastroenterol 2022;79:52-3. https://doi.org/10.4166/kjg.2014.059.e1

Evaluation on a supersaturatable self-microemulsifying (s-smdds) formulation of biphenyl dimethyl dicarboxylate (BDD) in Vitro and in Vivo

To enhance the dissolution and oral bioavailability of poorly water-soluble biphenyl dimethyl dicarboxylate (BDD), the supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed by adding a water-soluble polymer PVP to prevent precipitation of the drug and maintain a supersaturate state in vivo. Ternary phase diagrams were drawn to evaluate the microemulsification domain. The formulations were characterized by testing the physical stability of the drug, particle size and zeta potential. The pharmacokinetic study in beagle dogs was performed for the S-SMEDDS, SMEDDS formulation and the market drop pills. The optimized S-SMEDDS formulation consist of 35% (w/w) Cremphor EL35, 33% (w/w) Transcutol HP, 30% (w/w) MCT and 2% (w/w) PVPK30 of each excipient showed minimum mean droplet size (37.71 ± 0.87nm) and optimal drug release profile and better physical stability in water compared with the PVP absent SMEDDS. The in vivo studies showed that S-SMEDDS had significantly increased the Cmax and area under the plasma concentration-time curve (AUC) (P < 0.01). The S-SMEDDS formulation should be an effective oral dosage form for improving oral bioavailability of water-insoluble BDD.

Antidepressant potential of diphenyl dimethyl bicarboxylate (DDB) in a modified forced swimming test

Biphenyl Dimethyl Dicarboxylate (DDB); is an analogue of schisandrin C, a component isolated from Fructus Schisandrae Chinensis. It is now attracting growing attention for its polypharmacotherapeutic properties as an antiviral, hepatoprotective, and immunomodulator. It’s been additionally possessed neurobehavioral impacts on experimental animals. Thus, the wide use of DDB, along with its neurobehavioral impacts; has encouraged us to study its antidepressant potential using the forced swimming test (FST). Furthermore, the protocol for FST was modified by combining it with the tail suspension test. The effect of DDB (100 mg/kg/day, p.o., 7 days) on combined technique was evaluated against fluoxetine (15 mg/kg, i.p., single dose). In the end, the brains were dissected; serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels were measured. The results demonstrated that DDB decreased immobility in FST time as fluoxetine. Furthermore, DDB elevated 5HT, NE, and DA. DDB may be useful as a supportive antidepressant drug in hepatic diseased patients. However, more clinical studies are needed to ensure its safety.

Efficacy and Safety of Biphenyl Dimethyl Dicarboxylate and Ursodeoxycholic Acid Combination in Chronic Hepatitis Related to Metabolic Syndrome Components.

Steatohepatitis related to metabolic syndrome is a chronic liver disease prevalent in patients not only with non-alcoholic steatohepatitis but also with alcoholic liver disease and chronic viral hepatitis. On the other hand, there is limited data on the effects of hepatotonic agents in these patients. Therefore, this study evaluated the efficacy of a combined hepatotonic agent in this population. Thirty-three adults with chronic hepatitis and one or more components of metabolic syndrome were assigned randomly to receive biphenyl dimethyl dicarboxylate/ursodeoxycholic acid or a placebo for 24 weeks. The primary outcome was the normalization of ALT (≤40 U/L). The secondary outcomes were the change in controlled attenuation parameter, transient elastography, and Chronic Liver Disease Questionnaire score. The 33 patients were assigned randomly to two groups. Eight (50%) of 16 patients who received the intervention drug showed the normalization of ALT, whereas only one (6%) of 17 patients in the placebo group did so. In contrast, the change in controlled attenuation, transient elastography, and Chronic Liver Disease Questionnaire were similar in the two groups. ALT was changed significantly during the four assessment periods, and this change was affected by the group. The interaction between the group and time was also significant. AST was changed significantly during the same period. This change was not affected by the group. Biphenyl dimethyl dicarboxylate/ursodeoxycholic acid combination reduced ALT in chronic liver disease related to metabolic syndrome. On the other hand, there is no evidence that this leads to improved hepatic steatosis and fibrosis within 6 months.

Social behavior effects of diphenyl dimethyl bicarboxylate (DDB) in the sensory contact model

Sensory contact model (SCM) permits the evolution of diverse psychopathological states by the repeated antagonistic interactions between male mice. Biphenyl dimethyl dicarboxylate (DDB) is used as a hepatoprotective agent. The present work aimed to study the possible effects of DDB on social behavior developed by SCM by studying its effects on the transformation process to aggressive and submissive behaviors. Besides, measuring behavioral changes using the open field test (OFT) and the elevated plus maze test (EPM), neurochemical parameters [serotonin (5HT), norepqinephrine (NE), and dopamine(DA)], and immunological changes (total leucocyte count, differential leucocytic count, and evaluation of bone marrow lymphocytes count and viability assessment). Adult male Swiss mice were used; DDB was given in a dose of 100mg/kg by oral gavage daily for 2weeks from the fifth day to the last day of the SCM. The present study concluded that administration of DDB to the SCM involved animals was shown to be associated with significant positive impacts on the behavior of depressed partner in the SCM which were manifested by decreased latency and increased ambulation and rearing in OFT, increased number of entry in the open arm/total no of entries in EPM. This was associated with changes in brain levels of neurotransmitters which were manifested by increased NE and decreased DA, as well as the examined immunity related parameters which were manifested by increased total leucocyte count, bone marrow lymphocytes, and monocytes. So DDB can be used as a supportive antidepressant agent in patients with liver impairment and should be avoided in aggressive ones. However, more randomized controlled trials should be carried out to ascertain these effects.

Protective effect of Trillium tschonoskii saponin on CCl4-induced acute liver injury of rats through apoptosis inhibition

To explore hepatoprotective role and underlying mechanisms of Trillium tschonoskii Maxim (TTM), 36 rats were randomly divided into control, CCl4-induced liver injury model, and biphenyl dimethyl dicarboxylate (DDB) and low-, moderate-, and high-dose TTM treatment groups. After CCl4-induced model establishment, the rats from DDB and TTM groups were administrated with DDB at 0.2 g/kg per day and TTM at 0.1, 0.5, and 1.0 g/kg per day, while the rats from control and model groups were administrated with saline. After 5 days of treatments, all rats were sacrificed for determining serum ALT and AST levels and liver index, examining histopathological changes in liver through HE and TUNEL staining, and evaluating TNF-α and IL-6 mRNA expression by real-time PCR, and caspase-3, Bcl-2, and Bax expression by Western blot. Results indicated that CCl4 could induce acute liver injury and abnormal liver function in rats with obvious hepatomegaly, increased liver index, high ALT and AST levels, up-regulated TNF-α and IL-6, and overexpressed Bax and caspase-3. However, DDB and TTM could execute protective role in CCl4-induced liver injury in rats through reducing ALT and AST levels, rescuing hepatomegaly, down-regulating inflammatory factors and inhibiting hepatocyte apoptosis in a dose-dependent manner. Therefore, TTM has obvious protective role in CCl4-induced liver injury of rats through inhibiting hepatocyte apoptosis.

Effect of biphenyl dimethyl dicarboxylate and fluoxetine on performance of normally-fed and protein malnourished psychologically stressed mice in elevated plus maze

Stress alters psychological diseases such as anxiety and depression. Protein malnutrition (PM) contributes to psychological disorders. The present study aimed to investigate the effect of biphenyl dimethyl dicarboxylate (DDB) on anxiety of psychologically stressed protein malnourished mice as compared to its effect in normally-fed mice. Fluoxetine (FLX) was used as reference standard. Animals were randomly divided into two major groups, normally-fed group provided with 20% casein diet and a protein malnourished one was provided with a diet containing 8% casein for 21 consecutive days. The given diet was continued during the experiment. Stress was induced using the learned helplessness technique (LH). Each animal was exposed for 5days to the psychological stress session either alone or in association with drug administration following completion of 21days under the selected diet regimen. DDB and fluoxetine were given in doses of 100mg/kg p.o. and 10mg/kg i.p., respectively before exposure to foot shocks daily. Anxiety was evaluated using elevated plus maze (EPM) and the whole brain wet tissue monoamine levels, namely dopamine, norepinephrine and serotonin were estimated.Protein malnutrition in the presence of stress resulted in increasing number of open arm entries and head dipping as compared to the normally-fed stressed mice. Stress in the presence or absence of protein malnutrition significantly increased rearing frequency as compared to the corresponding mice. Fluoxetine in the presence of stress significantly decreased open arm time spent and number of open arm entries as compared to protein malnourished stressed mice. Protein malnutrition increased stretched attend posture.

The PERFECT Study (PEnnel Real liFe Efficacy Clinical Trial), a Double-Blind, Randomized, Multicenter Trial Examining the Efficacy of Biphenyl Dimethyl Dicarboxylate Combined with Garlic Oil in Patients with Transaminase Elevated Chronic Liver Disease

목적: 펜넬(Pennel(R))은 DDB에 마늘유(garlic oil)를 복합시킨 제제로 혈청 트랜스아미나제(AST와/또는 ALT)가 상승된 만성 간 질환자에서 펜넬의 치료 효과에 대한 유효성을 검증하기 위해 활성대조약인 레가론, 위약군과 비교 평가한 다 기관 제 4상 임상연구를 실시하였다. 방법: 총 11개 병원, 237명의 피험자가 연구에 참여하였다. 이 중 시험약군은 100명, 활성대조군은 102명, 위약군은 35명이었다. 12주간의 치료기간 동안 순응도는 좋았으며 중도 탈락은 없었다. 환자의 연령은 평균 46세, 남성의 비율이 높았다. 치료 전 ALT 값은 91 U/L였으며 66%가 비알코올성 지방간염, 15%가 알코올성 간염, 12%가 만성 C형간염 그리고 7%가 만성 B형간염 환자였다. 결과: 약물 투약 12주째 ALT 정상화 분율은 시험약군이 89명으로 89%, 활성대조군이 19명으로 18.6%, 위약군이 8명으로 22.9%로 나타났다(p < 0.001). 간염의 원인에 따른 분류에서도 시험군에서 통계적으로 의미 있게 ALT 정상화 분율의 비율이 높았다. 치료 전 대비 치료 12주의 ALT는 시험약군에서 평균 85 U/L 감소하였으나 활성대조군은 20 U/L, 위약군은 25 U/L 감소하였다. 항산화 효과 지표인 malondialdehyde(MDA)는 시험약군에서만 1.4 pmol/mg의 호전을 보였다. 하위그룹분석에서 비알코올성 지방간염과, 바이러스성 간염 환자에서 의미 있게 MDA 수치의 호전을 보였다(p < 0.001). 시험약물의 안전성 평가에서도 이상반응의 발생빈도가 위약군에 비해 차이가 없었다. 이상반응의 대부분은 감기, 피로, 설사 및 소화불량 등 grade 1의 경증이었으며 중대한 이상반응은 없었다. 삶의 질 평가 총점수도 시험약군이 치료 12주에 10점 이상 통계적으로 의미 있게 증가하였다(p < 0.001). 결론: 결론적으로 ALT가 상승한 만성 간 질환자를 대상으로 한 12주간의 펜넬 4상 임상 시험의 유효성과 안전성 평가에서 펜넬은 원인 질환과 무관하게 치료 4주 만에 급격한 ALT 수치의 정상화를 유도하였으며 항산화 효과를 보였다. 치료기간 동안 부작용이 거의 없는 안전한 약제로서 순응도가 뛰어났으며, 치료 후 삶의 질이 의미 있게 개선되는 효과를 보였다.

Self-Nanoemulsifying Drug Delivery System for Enhanced Bioavailability and Improved Hepatoprotective Activity of Biphenyl Dimethyl Dicarboxylate

Biphenyl Dimethyl Dicarboxylate (BDD) is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-nanoemulsifying drug delivery system (SNEDDS) containing BDD has been successfully prepared using carefully selected ingredients which are less affected by pH and ionic strength changes to improve its bioavailability. SNEDDS is an isotropic mixture of lipid, surfactant, and cosurfactant which are spontaneously emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo ternary phase diagrams composed of various excipients were plotted to identify self -nano -emulsifying area. Droplet size changes upon dilution with aqueous media and in vitro release of BDD from SNEDDS in 0.1N HCl and phosphate buffer (pH 7.4) were studied and compared with commercial chinese pilules and Pennel capsules. The hepatoprotective activity upon oral administration of SNEDDS against carbon tetrachloride-induced oxidative stress in albino rats was assessed by measuring biochemical parameters like serum glutamic oxalacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). Results showed that using a proper ratio of Tween 80 to Transcutol as surfactant and co-surfactant respectively and Miglyol 812 as oil to surfactants mixture resulted in production of infinitely diluted formulations in nano droplet size range. BDD self nano emulsified formula composed of 20% Miglyol 812, 60% Tween 80 and 20% Transcutol released 99% of the drug very rapidly within 10-15 minutes regardless of the pH condition. The oral absorption and bioavailability of BDD self nano emulsified formula in albino rats were significantly enhanced (P<0.01) with an average improvement of 1.7 and 6-folds that of commercial chinese pilules and Pennel capsules respectively. This improvement was also confirmed histopathologically in chemically injured rats and by the significant decrease in elevated liver enzymes level.

Aqueous solubility of poorly water-soluble drugs: Prediction using similarity and quantitative structure-property relationship models

The aqueous solubility of poorly water-soluble drugs is an important property of many factors affecting their bioavailability such as the solubility and rate of dissolution in water. The quantitative structure-property relationship approach using genetic algorithm was applied to make models for predicting some poorly water-soluble drugs such as ursodeoxycholic acid, diphenyl hydrantoin and biphenyl dimethyl dicarboxylate. The experimental solubility data of 3518 chemical structures were collected from the web and used to build a model. Three data sets of 50 compounds were extracted according to their structural similarity with each drug. A fast and predictive similarity based approach was developed and validated with conventional method. This can be used to predict the aqueous solubility for drugs by using a small set of compounds, especially for poorly water-soluble compounds. Moreover, the estimation values of various sets were further compared with fine grinding experiment data.

Improvement of bioavailability of water insoluble drugs: Estimation of intrinsic bioavailability (Short Communication)

A series of attempts to enhance the bioavailability of water insoluble drugs have been made by the fine grinding technique using a planetary ball mill in wet milling process. Here, the possibility of improving the dissolution properties of water insoluble drugs such as ursodeoxycholic acid (UDCA), diphenyl hydrantoin (phenytoin) and biphenyl dimethyl dicarboxylate (DDB) based on ultra-fine grinding process has been discussed with comparison to experimental data. Also examined was the intrinsic bioavailability estimated based on a molecular modeling approach and thermo- physical data.

慢性肝炎の Biphenyl Dimethyl Dicarboxylate 投与による臨床効果

慢性肝炎の Biphenyl Dimethyl Dicarboxylate 投与による臨床効果

Hepatoprotective and Anti-fatigue Effects of Lactic Acid Bacteria (Lactobacillus acidophilus, Bifidobacterium bifidum and Streptococcus thermophilus)

This study was carried out to investigate the effect of LAB (Lactic acid bacteria: Lactobacillus acidophilus, Bifidobacterium bifidum and Streptococcus thermophilus) on detoxication of damaged liver in carbon tetrachloride (<TEX>$CCl_4$</TEX>) and ethanol (25%)-treated rats. Rats had been daily (twice a day) pre-treated with saline (0.5 ml/kg: untreated group), <TEX>$CCl_4$</TEX> (0.5 ml/kg: other groups) for 6 days. At seventh day, after treating rat with <TEX>$CCl_4$</TEX> and then, mixture of LAB (<TEX>$10^{11}$</TEX>/0.5 ml: LAB group), saline (0.5 ml/kg: untreated group, <TEX>$CCl_4$</TEX> group), and biphenyl dimethyl dicarboxylate (DDB) (50 mg/kg: DDB group) were treated orally with <TEX>$CCl_4$</TEX> for 8 days. Ethanol is treated as the same manner instead of <TEX>$CCl_4$</TEX>. To investigate the hepatoprotective effect, rats treated with <TEX>$CCl_4$</TEX> and ethanol were analyzed with serum GOT and GPT level. The GOT and GPT levels of LAB group was lower than the level of <TEX>$CCl_4$</TEX> and DDB group. Especially, compared with data of <TEX>$CCl_4$</TEX> group, GPT activity showed statistically significant result in the significance level of p < 0.05. The LAB group treated with ethanol also showed lower level of GOT and GPT than the other control groups treated with ethanol. The triglyceride level of serum decreased more in a group treated special materials (DDB and LAB group) than ethanol group. As well, the effect of LAB on the antifatigue has been investigated. The animals (10/group) were divided into 4 groups (untreated group, Carrier group, Red-ginseng group, LAB group). Each group was given carrier (0.9 mg/0.2 ml), red ginseng extract (200 mg/kg), and mixture of LAB (<TEX>$10^{11}$</TEX>/0.2 ml). Special materials were given for three weeks. After finishing treating through oral, horizontal wire test, rotarod test, and forced swimming test were performed. The time of resistance to fatigue of the group, fed with mixture of LAB, was longer than the time when mice treated with red-ginseng that the effect was already revealed. The result of this study revealed that LAB could decrease hepatocelluar injury compared with rats treated orally with <TEX>$CCl_4$</TEX> and ethanol, and could also decrease fatigue.

Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15

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 microg/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 microg/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.

Regulation of Inflammatory Repertoires and NF-κB Signal Transduction by DDB, an Active Compound from Schizandra Chinensis Baillon

Background: Chronic inflammation in the brain has known to be associated with the development of a various neurological diseases including dementia. In general, the characteristic of neuro-inflammation is the activated microglia over the brain where the pathogenesis occurs. Pro-inflammatory repertoires, interleukin-1 (IL-1) and nitric oxide (NO), are the main causes of neuro-degenerative disease, particularly in Alzheimer's disease (AD) which is caused by neuronal destruction. Those pro-inflammatory repertoires may lead the brain to chronic inflammatory status, and thus we hypothesized that chronic inflammation would be inhibited when pro-inflammatory repertoires are to be well controlled by inactivating the signal transduction associated with inflammation. Methods: In the present study, we examined whether biphenyl dimethyl dicarboxylate (DDB), an active compound from Schizandra chinensis Baillon, inhibits the NO production by a direct method using Griess reagent and by RT-PCR in the gene expression of inducible nitric oxide synthase (iNOS) and IL-1. Western blots were also used for the analysis of NF- and I. Results: In the study, we found that DDB effectively inhibited IL-1 as well as NO production in BV-2 microglial cell, and the translocation of NF- was comparably inhibited in the presence of DDB comparing those to the positive control, lipopolysaccharide. Conclusion: The data suggested that the DDB from Schizandra chinensis Baillon may play an effective role in inhibiting the pro-inflammatory repertoires which may cause neurodegeneration and the results imply that the compound suppresses a cue signal of the microglial activation which can induce the brain pathogenesis such as Alzheimer's disease.

The potential anti-HBV effect of amantadine in combination with ursodeoxycholic acid and biphenyl dimethyl dicarboxylate in HepG2 2.2.15 cells

Experimental studies have demonstrated that the triple combination of amantadine (A)/ ursodeoxycholic acid (UDCA, U)/ biphenyl dimethyl dicarboxylate (DDB, D) might have a preferential antiviral effect compared with that observed in interferon-induced antiviral signal pathways, such as those of STAT1alpha and the 6-16 genes. To confirm the result, this study examined whether the signal transduction for the antiviral activity in HepG2 2.2.15 was induced dependently or independently of interferon. To accomplish this, the correlation between the STAT1alpha and 6-16 genes, and nitric oxide, for the mediation of the antiviral activity was assessed. The increase in nitric oxide in the UDCA groups suggests that the inhibition of viral gene replication was enhanced by the amantadine combinations (AU and AUD), and might be more effective if incubated for longer periods. It was found that STAT1alpha was activated by the amantadine combination, although to a lesser extent than that of interferon-alpha, and the primary endpoints examined for the inhibition of gene expression (HBsAg and HBcAg) were remarkably well regulated. This suggests that the amantadine triple, or at least the double, combination had better clinical benefits than those of IFN-alpha and the nucleoside analogue single treatment. This demonstrates that the amantadine combination might be a substitute for the existing HBV therapy if the results of in vivo and in vitro studies concur.

Anti-lipid peroxidation and protection of liver mitochondria against injuries by picroside II

To investigate the anti-lipid peroxidation and protection of liver mitochondria against injuries in mice with liver damage by picroside II. Three animal models of liver damage induced by carbon tetrachloride (CCl(4): 0.1 mL/10 g, ip), D-galactosamine (D-GalN: 500 mg/kg, ip) and acetaminophen (AP: 0.15 g/kg, ip) were respectively treated with various concentrations of picroside II (5, 10, 20 mg/kg, ig). Then we chose the continuously monitoring method (recommended by International Clinical Chemistry League) to analyze serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values, Marland method to detect the activity of manganese-superoxide dismutase (SOD) in liver mitochondria, TBA colorimetry to determine the content of malonicdialdehyde (MDA) in liver tissue, DTNB method to evaluate the activity of glutathioneperoxidase (GSH-Px) and Lowry method to detect protein level in liver tissue. Meanwhile, effects of picroside II on the activity of ATPase and swelling extent of mitochondria in hepatocytes damaged by AP were also evaluated. Picroside II could significantly prevent liver toxicity in the three models of liver damage. It decreased the high levels of ALT and AST in serum induced by the administration of CCl(4), D-GalN and AP, reduced the cellular damage of liver markedly, and appeared to be even more potent than the positive control drug of biphenyl dimethyl dicarboxylate pilules (DDB). In groups treated with different doses of picroside II, compared to the model group, the content of MDA in serum decreased evidently, whereas the content of SOD and GSH-Px increased in a dose-dependent manner, and the difference was statistically significant. Further, in the study of AP model, picroside II inhibited AP-induced liver toxicity in mice, enhanced the activity of ATPase, improved the swelling extent of mitochondria and helped to maintain a normal balance of energy metabolism. Picroside II can evidently relieve hepatocyte injuries induced by CCl(4), D-GalN and AP, help scavenge free radicals, protect normal constructions of mitochondria membrane and enhance the activity of ATPase in mitochondria, thereby modulating the balance of liver energy metabolism, which might be part of the mechanisms of hepatoprotective effects of picroside II.

A polymeric micellar carrier for the solubilization of biphenyl dimethyl dicarboxylate.

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, 1 K), 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 dialy-sis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1 K 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.