Lamivudine Therapy Exacerbates Bilirubinemia in Patients Underlying Severely Advanced Hepatitis.

Lamivudine belongs to the set of antiviral agents effective against hepatitis B virus infection. Given case reports on liver injuries after certain antiviral agent treatments, this study examined the effects of lamivudine on alanine aminotransferase (ALT) and total bilirubin (TB) using a medical system database. A total of 1,321 patients taking lamivudine alone or with others were evaluated using laboratory hits in an electronic medical system at Seoul National University Hospital from 2005 through 2011. The patients were grouped according to prior ALT results: G#1, ALT < 40 IU/L; G#2, 40 IU/L ≤ ALT < 120 IU/L; G#3, 120 IU/L ≤ ALT < 240 IU/L; and G#4, ALT ≥ 240 IU/L. In G#1 and G#2 patients, lamivudine or adefovir treatment decreased ALT and TB compared to prior values. In G#3 and G#4 patients with three times the upper limit of normal (ULN) ≤ ALT < 15 times the ULN, both ALT and TB were decreased after treatment with lamivudine alone, or adefovir following lamivudine therapy, indicating that lamivudine therapy ameliorated liver functions. However, in G#4 patients who experienced severely advanced hepatitis (ALT ≥ 15 times the ULN, or ≥ 600 IU/L), lamivudine augmented TBmax (6.3→13.3 mg/dL) despite a slight improvement in ALT (839→783 IU/L), indicative of exacerbation of bilirubinemia. Patients who used adefovir after lamivudine also showed a high incidence of hyperbilirubinemia when they experienced severely advanced hepatitis. Treatment with adefovir alone did not show the effect. In conclusion, lamivudine may increase the risk of hyperbilirubinemia in patients with severely advanced hepatitis, implying that caution should be exercised when using lamivudine therapy in certain patient populations.

Protective effects of rosmarinic acid against hydrogen peroxide­induced cellular senescence and the inflammatory response in normal human dermal fibroblasts.

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) that induces numerous cellular events, including cellular senescence and inflammatory responses. Therefore, the aim of this study was to investigate the protective effect of Rosmarinic acid (RA) in H2O2­induced oxidative stress in normal human dermal fibroblasts (NHDFs). Cytotoxicity assays were performed using a water­soluble tetrazolium salt, and senescence­associated ß­galactosidase activity was determined to investigate the proportion of senescent cells. Antioxidant capacities were evaluated via H2O2­scavenging activity, reverse transcription­quantitative polymerase chain reaction, NRF2 luciferase reporter gene activity and intracellular ROS scavenging assays. Cytokine­coded gene expression analysis and nuclear factor­κB luciferase activity were determined to verify the anti­inflammatory effect of RA. As a result, the present study demonstrated that rosmarinic acid inhibited H2O2­induced oxidative stress and inflammatory responses in normal human dermal fibroblasts. Initially, the doses of RA that exerted minimal cytotoxic effects in NHDFs were determined using a cytotoxicity assay. Subsequently, pretreatment with the appropriate doses of RA significantly reversed the H2O2­induced decrease in NHDF cell viability and decreased cellular senescence of NHDFs. In addition, RA inhibited H2O2­induced ROS production in NHDFs, as determined by a ROS scavenging assay. The protective effects of RA were mediated by the inhibition of nuclear factor erythroid­derived 2­like 2, a transcription factor that functions as a key regulator of redox sensitivity. Furthermore, RA suppressed H2O2­induced inflammation in NHDFs and significantly rescued H2O2­induced downregulation of sirtuin 1. RA also inhibited nuclear factor (NF)­κB transcriptional activity and the expression of NF­κB target genes, including tumor necrosis factor­α and interleukin­6, in H2O2­exposed NHDFs. Taken together, these data indicate that RA inhibits H2O2­induced cellular damage in NHDFs.

Topical application of a cleanser containing extracts of Diospyros kaki folium, Polygonum cuspidatum and Castanea crenata var. dulcis reduces skin oil content and pore size in human skin.

The effects of skin pores on skin topographic features can be reduced by decreasing excessive production and accumulation of sebum and elimination of comedones. Therefore, a cosmetic cleanser that regulates sebum homeostasis is required. In the present study, the effects of a cosmetic cleanser that contained Diospyros kaki folium, Polygonum cuspidatum and Castanea crenata var. dulcis (DPC) was examined on the removal of sebum and on skin pore size. Healthy volunteers (n=23) aged 20-50 years were asked to apply the test materials to the face. Skin oil content, pore size, pore number and extracted sebum surface area were measured using various measurement methods. All the measurements were performed at pre- and post-application of the test materials. When the cosmetic cleanser containing DPC was applied to the skin, the oil content decreased by 77.3%, from 6.19 to 1.40. The number of skin pores decreased by 24.83%, from 125.39 to 94.23. Skin pore size decreased from 0.07 to 0.02 µm3 (71.43% decrease). The amount of extracted sebum increased by 335% when the DPC cleanser was used. Compared to the control cleanser, skin oil content was significantly decreased when the cleanser that contained DPC was used. The cleanser containing DPC also decreased pore size and number. Finally, the DPC cleanser easily removed solidified sebum from the skin.

Aminolysis of 4-nitrophenyl phenyl carbonate and thionocarbonate: effects of amine nature and modification of electrophilic center from C[double bond]O to C[double bond]S on reactivity and mechanism.

A kinetic study is reported for the reactions of 4-nitrophenyl phenyl carbonate (5) and thionocarbonate (6) with a series of alicyclic secondary amines in 80 mol% H(2)O-20 mol% DMSO at 25.0 +/- 0.1 degrees C. The plots of k(obsd) vs. amine concentration are linear for the reactions of 5. On the contrary, the plots for the corresponding reactions of 6 curve upward as a function of increasing amine concentration, indicating that the reactions proceed through two intermediates (i.e., a zwitterionic tetrahedral intermediate T(+/-) and its deprotonated form T(-)). The Brønsted-type plot for 5 the reactions of with secondary amines exhibits a downward curvature, i.e., the slope decreases from 0.98 to 0.26 as the pK(a) of the conjugate acid of amines increases, implying that the reactions proceed through T(+/-) with a change in the rate-determining step (RDS). The k(N) values are larger for the reactions of with secondary amines than for those with primary amines of similar basicity. Dissection of k(N) values for the reactions of 5 into the microscopic rate constants (i.e., k(1) and k(2)/k(-1) ratio) has revealed that k(1) is larger for the reactions with secondary amines than for those with isobasic primary amines, while the k(2)/k(-1) ratio is nearly identical. On the other hand, for reactions of 6, secondary amines exhibit larger k(1) values but smaller k(2)/k(-1) ratios than primary amines. The current study has shown that the reactivity and reaction mechanism are strongly influenced by the nature of amines (primary vs. secondary amines) and electrophilic centers (C[double bond]O vs. C[double bond]S).

Effect of changing electrophilic center from C=O to C=S on rates and mechanism: pyridinolyses of O-2,4-dinitrophenyl thionobenzoate and its oxygen analogue.

Second-order rate constants have been measured spectrophotometrically for the reactions of O-2,4-dinitrophenyl thionobenzoate (1) and 2,4-dinitrophenyl benzoate (2) with a series of substituted pyridines in 80 mol % H(2)O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. The Brønsted-type plots obtained are nonlinear with beta(1) = 0.26, beta(2) = 1.07, and pK(a) degrees = 7.5 for the reactions of 1 and beta(1) = 0.40, beta(2) = 0.90, and pK(a) degrees = 9.5 for the reactions of 2, suggesting that the pyridinolyses of 1 and 2 proceed through a zwiterionic tetrahedral intermediate T(+/-) with a change in the rate-determining step at pK(a) degrees = 7.5 and 9.5, respectively. The thiono ester 1 is more reactive than its oxygen analogue 2 except for the reaction with the strongest basic pyridine studied (pK(a) = 11.30). The k(1) value is larger for the reactions of 1 than for those of 2 in the low pK(a) region, but the difference in the k(1) value becomes negligible with increasing the basicity of pyridines. On the other hand, 1 exhibits slightly larger k(2)/k(-1) ratio than 2 in the low pK(a) region but the difference in the k(2)/k(-1) ratio becomes more significant with increasing the basicity of pyridines. Pyridines are more reactive than alicyclic secondary amines of similar basicity toward 2 in the pK(a) above ca. 7.2 but less reactive in the pK(a) below ca. 7.2. The k(1) value is slightly larger, but the k(2)/k(-1) ratio is much smaller for the reactions of 2 with pyridines than with isobasic secondary amines in the low pK(a) region, which is responsible for the fact that the weakly basic pyridines are less reactive than isobasic secondary amines.

Reinterpretation of curved Hammett plots in reaction of nucleophiles with aryl benzoates: change in rate-determining step or mechanism versus ground-state stabilization.

A kinetic study is reported for the reaction of the anionic nucleophiles OH-, CN-, and N 3 - with aryl benzoates containing substituents on the benzoyl as well as the aryloxy moiety, in 80 mol % H2O - 20 mol % dimethyl sulfoxide at 25.0 degrees C. Hammett log k vs sigma plots for these systems are consistently nonlinear. However, a possible traditional explanation in terms of a mechanism involving a tetrahedral intermediate with curvature resulting from a change in rate-determining step is considered but rejected. The proposed explanation involves ground-state stabilization through resonance interaction between the benzoyl substituent and the electrophilic carbonyl center in the two-stage mechanism. Accordingly, the data are nicely accommodated on the basis of the Yukawa-Tsuno equation, which gives linear plots for all three nuceophiles. Literature reports of the mechanism of acyl transfer processes are reconsidered in this light.