Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study.

AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Proton polarization with p-terphenyl crystal by integrated solid effect on photoexcited triplet state.

We have carried out the experiments for polarizing protons in single crystals of p-terphenyl doped with 0.1 mol% pentacene. The experiments have been performed in a magnetic field of 3 kG at room temperature or at 77 K. We obtained the polarization of 1.3% for protons in bulk at room temperature by using a pulsed dye-laser with the wavelength of 590 nm, the average power of 150 mW, and the repetition rate of 50 Hz. The polarization at 77 K reached 18% by irradiation with the dye-laser of 500 mW, 50 Hz and the same wavelength. The polarization of protons was measured by the neutron transmission method also. The result was consistent with that measured by the nuclear magnetic resonance.

Phenytoin potentiates interleukin-1-induced prostaglandin biosynthesis in human gingival fibroblasts.

1. The effect of phenytoin (PHT) on prostaglandin E2 (PGE2) biosynthesis in human gingival fibroblasts stimulated by interleukin-1 (IL-1 alpha, IL-1 beta) or by tumour necrosis factor alpha (TNF alpha) was studied. 2. IL-1 alpha (1.5-6.0 ng ml-1) and IL-1 beta (30-300 pg ml-1), dose-dependently, stimulated PGE2 formation, in 24 h cultures, with IL-beta being the most potent agonist. 3. PHT (2.5-20 micrograms ml-1) did not induce PGE2 formation itself but potentiated IL-1 alpha- and IL-1 beta-induced PGE2 formation in the gingival fibroblasts in a manner dependent on the concentrations of both IL-1 and PHT. 4. IL-1 beta (0.1-1.0 ng ml-1) induced release of [3H]-arachidonic acid ([3H]-AA) from prelabelled fibroblasts that was potentiated by PHT (20 micrograms ml-1). 5. TNF-alpha (greater than or equal to 0.01 micrograms ml-1) significantly stimulated the biosynthesis of PGE2 by a process that was potentiated by PHT. 6. Addition of exogenous arachidonic acid (AA) (greater than or equal to 1 microM) caused an increase of PGE2 formation in the fibroblasts that was not potentiated by PHT (20 micrograms ml-1). 7. The results indicate that treatment with PHT results in upregulation of prostaglandin biosynthesis in gingival fibroblasts challenged with IL-1 or TNF alpha, at least partly due to enhanced level of phospholipase A2 activity.

High proton polarization by microwave-induced optical nuclear polarization at 77 K

Protons in naphthalene and p-terphenyl doped with pentacene have been polarized up to 32% and 18%, respectively, at liquid nitrogen temperature in a magnetic field of 0.3 T by means of microwave-induced optical nuclear polarization. The polarization was measured by nuclear magnetic resonance as well as by the neutron transmission method. The relaxation time of the proton polarization at 0.0007 T and 77 K was found to be almost 3 h and the polarization enhancement reached a record value of 8x10(4). The usefulness of the method in many areas of physics and chemistry is discussed.

Antibacterial activity of hydroxychalcone against methicillin-resistant Staphylococcus aureus.

Anti-candidal hydroxychalcone, 2,4,2'-trihydroxy-5'-methylchalcone (THMC), was investigated for its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). THMC showed the minimum inhibitory concentrations of 25.0-50.0 mug/ml against tested 20 strains, at which the effect was based on a bacteriostatic action. THMC of 25.0 mug/ml completely inhibited the incorporation of radio-labelled thymidine and uridine into MRSA cells. In combination with antibiotics, the fractional inhibitory concentration indices were 0.47 for gentamicin and 0.79 for vancomycin, indicating that THMC acts synergistically with these agents. THMC would be a potent therapeutic agent for MRSA infections.

Two flavonol glycosides, hexandrasides C and D, from the underground parts of Vancouveria hexandra.

In addition to four known glycosides, icariin, epimedin B, epimedosides A and E, two new glycosides of a flavonol with a gamma,gamma-dimethylallyl group were isolated from the underground parts of Vancouveria hexandra. The structures were determined to be des-O-methyl-anhydroicaritin 3-O-beta-D-xylopyranosyl(1----2)-alpha-L-rhamnopyranoside 7-O-beta-D-glucopyranosyl(1----2)-beta-D-glucopyranoside and anhydroicaritin 3-O-alpha-L-rhamnopyranosyl(1----3)-alpha-L-rhamnopyranoside 7-O-beta-D-glucopyranoside by means of spectral analysis.

Oligostilbenoids in stem bark of Vatica rassak.

Three resveratrol oligomers, vaticanols. A, B and C, as well as three known stilbenoids, resveratrol, piceid and epsilon-viniferin were isolated from the stem bark of Vatica rassak (Dipterocarpaceae). Their structures were determined by the analysis of NMR spectral data including the application of 2D methods.

Two flavonol glycosides from Vancouveria hexandra.

In addition to two known glycosides, ikarisoside F and epimedin A, two new glycosides of a flavonol with a gamma, gamma-dimethylallyl group were isolated from the underground and the aerial parts of Vancouveria hexandra. The structures were determined to be des-O-methylanhydroicaritin 3,7-diglucoside and anhydroicaritin 3-glucosyl (1----3)rhamnoside-7-glucoside by means of spectral analysis.

Two flavonol glycosides from the underground parts of Vancouveria hexandra.

Two new flavonol glycosides were isolated from the roots and rhizomes of Vancouveria hexandra. The glycosides were determined by chemical and spectral means to be anhydroicaritin 3-galactosyl(1----3) rhamnoside-7-glucoside and anhydroicaritin 3-[6-O-acetyl-galactosyl(1----3)rhamnoside]-7-glucoside.

Stilbene oligomers in roots of Sophora davidii.

Three stilbene oligomers, davidiols A-C were isolated from the roots of Sophora davidii in addition to the seven known phenols, leachianone A, sophoraflavanones G, H and I, miyabenol C, alpha-viniferin and epsilon-viniferin. Their structures and relative configurations were established by means of 2D-NMR spectroscopy including COLOC and PSNOESY.

Anti-oral microbial activity of isoflavonoids in root bark of Ormosia monosperma.

From the root bark of Ormosia monosperma, 10 isoflavonoids including two new compounds 7,4'-dihydroxy-6",6"-dimethylpyrano-(2",3":5,6)-8-(3-methyl-1,3- butadienyl)isoflavone, named ormosidin, and dalbergion 4'-O-beta-D-glucopyranoside, were isolated. These structures were confirmed by spectroscopic analysis. 2,3-Dihydroauriculatin, one of the compounds isolated, showed moderate activities against oral-microbial organisms (Streptococcus mutans, Prophyromonas gingivalis and Actinomyces actinomycetemcomitans).

Four flavonol glycosides from Achlys triphylla.

Four new flavonol glycosides were isolated from the underground parts of Achlys triphylla in addition to eight known compounds. By means of spectroscopic analysis, the structures were characterized as isorhamnetin 3-glucosyl(1----3)galactoside, isorhamnetin 3-[6''acetylglucosyl(1----3)galactoside], isorhamnetin 3-[4''6''-di-acetylglucosyl(1----3)galactoside], and syringetin 3-[6''-acetylglucosyl(1----3)galactoside], respectively. In the aerial parts of the plant, seven known compounds were also confirmed.

Flavonol glycoside production in callus cultures of Epimedium diphyllum.

Callus cultures of Epimedium diphyllum produced a large amount of epimedoside A in addition to a small amount of diphylloside B, ikarisoside C, epimedoside E, diglycosides of des-O-methylanhydroicaritin (8-gamma, gamma-dimethylallylkaempfero). Icariin, epimedins A-C, which are glycosides of anhydroicaritin, were also produced in the callus cultures. Contents of the flavonol glycosides in callus tissue were higher than those of mother plants, but the composition of each flavonol glycoside mixture in the callus cultures was different from that of the original plants. The time-course experiments showed that an inverse relationship existed between cell growth and flavonol glycoside production. Effects of hormonal factors on cell growth and flavonol glycoside production indicated that 2,4-dichlorophenoxyacetic acid was needed for the production of flavonol glycosides.

Stilbenoids in the stem bark of Hopea parviflora.

From the bark of Hopea parviflora, two stilbenoids, named (+)-parviflorol and (-)-ampelopsin A, were isolated in addition to three known compounds: (+)-balanocarpol, (-)-epsilon-viniferin and (-)-hopeaphenol. Their structures were determined by analysis of spectral data, including 2D NMR and NOE experiments, respectively.

Hepatic actinomycosis: case report and review of the literature in Japan.

Hepatic actinomycosis is rare. We report an 86-year-old Japanese man with a 3-day history of high fever and anorexia who had an actinomycotic liver abscess complicated by disseminated intravascular coagulation (DIC). A definitive diagnosis was made when an Actinomyces species was cultured from aspirated pus. The clinical course was satisfactory. Treatment included prompt percutaneous drainage coupled with long-term intravenous administration of high-dose minocycline and piperacillin, combined with therapy for DIC. We reviewed 11 cases in Japan of Actinomyces involving the liver, including the case reported here. In most patients, there were no predisposing factors. Common symptoms and laboratory findings included fever, abdominal pain, leukocytosis, and elevated C-reactive protein. In 6 of the 11 patients a partial hepatectomy was performed because hepatic tumor was suspected. Five patients presented with a liver abscess. Hepatic actinomycosis should be considered in the differential diagnoses of pyogenic liver abscess and space-occupying lesions of the liver.

The phenytoin metabolite p-HPPH upregulates prostaglandin biosynthesis in human gingival fibroblasts challenged to interleukin-1.

The effects of and interactions between the major phenytoin (PHT) metabolite 5-parahydroxyphenyl-5-phenylhydantoin (p-HPPH) and interleukin-1 (IL-1 alpha, IL-1 beta) or tumor necrosis factor alpha (TNF alpha) on prostaglandin biosynthesis in human gingival fibroblasts were studied. IL-1 alpha, IL-1 beta and TNF alpha, dose-dependently, stimulated PGE2 formation in gingival fibroblasts. The metabolite, p-HPPH (1.2-2.4 micrograms/ml), did not induce PGE2 formation itself but potentiated IL-1 alpha and IL1 beta induced PGE2 formation in the gingival fibroblasts in a manner dependent on the concentration of both IL-1 and p-HPPH. The metabolite also stimulated IL-1 induced formation of 6-Keto PGF1 alpha, the stable breakdown product of PGI2, in a dose dependent manner. IL-1 beta induces release of [3H]-arachidonic acid ([3H]-AA) from prelabelled fibroblasts, which was potentiated by p-HPPH (> or = 1.2 micrograms/ml). TNF alpha (> or = 1 ng/ml) significantly stimulated the biosynthesis of PGE2 by a process that was also potentiated by p-HPPH. Addition of exogenous, unlabelled AA (10 microM) caused an increase of PGE2 formation in the fibroblasts that was not potentiated by p-HPPH (1.6 micrograms/ml). The results indicate that treatment with p-HPPH results in upregulation of prostaglandin synthesis in gingival fibroblasts challenged to IL-1 or TNF alpha at the level of phospholipase A2.

Antibacterial activity of xanthones from guttiferaeous plants against methicillin-resistant Staphylococcus aureus.

Extracts of Garcinia mangostana (Guttiferae) showing inhibitory effects against the growth of S. aureus NIHJ 209p were fractionated according to guidance obtained from bioassay and some of the components with activity against methicillin-resistant Staphylococcus aureus (MRSA) were characterized. One active isolate, alpha-mangostin, a xanthone derivative, had a minimum inhibitory concentration (MIC) of 1.57-12.5 micrograms mL-1. Other related xanthones were also examined to determine their anti-MRSA activity. Rubraxanthone, which was isolated from Garcinia dioica and has a structure similar to that of alpha-mangostin, had the highest activity against staphylococcal strains (MIC = 0.31-1.25 micrograms mL-1), an activity which was greater than that of the antibiotic vancomycin (3.13-6.25 micrograms mL-1). The inhibitory effect against strains of MRSA of two of the compounds when used in conjunction with other antibiotics was also studied. The anti-MRSA activity of alpha-mangostin was clearly increased by the presence of vancomycin; this behaviour was not observed for rubraxanthone. The strong in-vitro antibacterial activity of xanthone derivatives against both methicillin-resistant and methicillin-sensitive Staphylococcus aureus suggests the compounds might find wide pharmaceutical use.

Flavanones with potent antibacterial activity against methicillin-resistant Staphylococcus aureus.

With the therapeutic concept of using the defensive ability of plants against microbial infections, phytoalexin, an antimicrobial phytochemical was studied for its ability to inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA). Extracts from Sophora exigua (Leguminosae) were fractionated by serial chromatography and the anti-MRSA activity of each fraction was determined by the agar-plate method. Among the active isolates, 5,7,2',6'-tetrahydroxy-6-isoprenyl-8-lavandulyl-4'-methox yflavanone (exiguaflavanone D) completely inhibited the growth of all the MRSA strains examined at the concentration of 1.56-6.25 micrograms mL-1, and 5, 2',6'-trihydroxy-8-lavandulyl-7-methoxy-flavanone (exiguaflavanone B) inhibited at a concentration of 50 micrograms mL-1. This former compound is expected to be a phytotherapeutic agent for MRSA infections as an alternative to conventional antibiotics with unwanted side-effects or the appearance of antibiotic-resistant bacteria.

Comparative study on the antibacterial activity of phytochemical flavanones against methicillin-resistant Staphylococcus aureus.

Differently substituted flavanones were isolated from Leguminosae and their antibacterial activity was comparatively studied against methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MICs) of phytochemical flavanones to clinical isolates of MRSA were determined by a serial agar dilution method. The structure-activity relationship has indicated that 2',4'- or 2',6'-dihydroxylation of the B ring and 5,7-dihydroxylation of the A ring in the flavanone structure are important for significant anti-MRSA activity and that substitution with a certain aliphatic group at the 6- or 8-position also enhances the activity. Among the thirteen flavanones tested, tetrahydroxyflavanones with these structural characteristics isolated from Sophora exigua and Echinosophora koreensis showed intensive activity to inhibit the growth of all MRSA strains at 3.13-6.25 micrograms/ml. The present hydroxyflavanones would be useful in the phytotherapeutic strategy against MRSA infections.

Flavones with antibacterial activity against cariogenic bacteria.

Methanolic extracts obtained from 13 plants were studied for their antibacterial activity against cariogenic bacteria. Among them, the extract from Artocarpus heterophyllus showed the most intensive activity. Serial chromatographic purifications offered two active compounds which were identified as 6-(3-methyl-1-butenyl)-5,2',4'-trihydroxy-3-isoprenyl-7-methoxy flavone and 5,7,2',4'-tetrahydroxy-6-isoprenylflavone. Both isolates completely inhibited the growth of primary cariogenic bacteria at 3.13-12.5 micrograms/ml. They also exhibited the growth inhibitory effects on plaque-forming streptococci. These phytochemical isoprenylflavones would be potent compounds for the prevention of dental caries.