Kinetics of photooxidation of papaverine hydrochloride and its major photooxidation products

HPCE methodology was modified to be used in kinetic experiments on photooxidation reactions of papaverine hydrochloride 1 and its oxidation products (papaverinol 2 and papaveraldine hydrochloride 3) chloroform solutions exposed to UV254 light in aerobic conditions. On photooxygenation of the above compounds is formed the final degradation product, a brown compound X 4, 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinylim chloride. The rate of 4 formation from the above compounds can be given as 2>3>1>1 HCl. The photooxidation reactions of 1 and 2 proceed with pseudo first-order kinetics and that reaction for 3 follows zero-order kinetics. The most labile compound is 2 whose half-life time is 2.4 times shorter than that one of 1 HCL. The most stable product is 3 whose half-life time is 31-fold longer than of 2. The specific quantum yields are equal 0.28, 0.30 and 0.10 for 1 HCl, 2 and 3, respectively which confirm the above stability pattern of the compounds concerned.     

Crystal forms of ketorolac

Four crystal forms of ketorolac have been obtained by recrystallization in organic solvents under variable conditions. Different ketorolac polymorphs and pseudopolymorph were characterized by X-ray powder diffraction crystallography (XRD), Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In the dissolution studies in water at 37 +/- 0.5 degrees C, four crystal forms showed different patterns. The solubility of Form I were the highest. The solubility decreased in rank order: Form I > Form II > Form III > Form IV. Form land Form III were shown to have a good physical stability at room temperature for 60 days. However, Form II is converted to Form III and Form IV is converted to Form I after 60 days storage. Therefore, these observations indicate that crystalline polymorphism for ketorolac is readily inter-convertible and the relationship may have to taken into consideration in the formulation of the drug.     

Hepatic arterial infusion chemotherapy in gastric cancer: a report of four cases and analysis of the literature

AIMS AND BACKGROUND: Gastric cancer is associated with high mortality. Although the liver is a common site of metastases in this tumor, the experience with liver-directed therapies is limited. METHODS: We report a single-center experience involving four patients with liver metastases from gastric cancer treated by hepatic arterial infusion (HAI). In addition, we performed a search for reports on HAI in gastric cancer metastatic to the liver and used the studies with data on survival of individual patients for a pooled analysis. RESULTS: Among three valuable patients, one had a complete response, one had stable disease and one had progressive disease. The patient with complete response is still alive 41 months after the diagnosis of liver metastases, while the other patients died 6, 22 and 31 months after the diagnosis. Objective responses were observed in 48% of the 25 patients in the pooled analysis. Objective response and limited hepatic involvement were independent predictors of survival in these patients. CONCLUSIONS: Although isolated liver involvement in metastatic gastric cancer is rare, HAI seems to be similarly effective in these patients as in patients with liver metastases from colorectal cancer. The prognosis is significantly better in gastric cancer patients who have limited hepatic involvement and attain an objective response after HAI.     

Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes

Background

Early clinical trials, mostly in the setting of melanoma, have shown that dendritic cells (DCs) expressing tumor antigens induce some immune responses and some clinical responses. A major difficulty is the extension to other tumors, such as breast carcinoma, for which few defined tumor-associated antigens are available. We have demonstrated, using both prostate carcinoma and melanoma as model systems, that DCs loaded with killed allogeneic tumor cell lines can induce CD8⁺ T cells to differentiate into cytotoxic T lymphocytes (CTLs) specific for shared tumor antigens.

Methods

The present study was designed to determine whether DCs would capture killed breast cancer cells and present their antigens to autologous CD4⁺ and CD8⁺ T cells.

Results

We show that killed breast cancer cells are captured by immature DCs that, after induced maturation, can efficiently present MHC class I and class II peptides to CD8⁺ and CD4⁺ T lymphocytes. The elicited CTLs are able to kill the target cells without a need for pretreatment with interferon gamma. CTLs can be obtained by culturing the DCs loaded with killed breast cancer cells with unseparated peripheral blood lymphocytes, indicating that the DCs can overcome any potential inhibitory effects of breast cancer cells.

Conclusion

Loading DCs with killed breast cancer cells may be considered a novel approach to breast cancer immunotherapy and to identification of shared breast cancer antigens.

     

Extraaxial neurofibromas versus neurilemmomas: discrimination with MRI

OBJECTIVE: The purpose of our study was to evaluate whether MRI can discriminate between extraaxial neurofibromas and neurilemmomas. MATERIALS AND METHODS: MR images of 52 patients with a pathologically proven extraaxial neurofibroma or neurilemmoma were retrospectively reviewed by observers who were unaware of the surgical results, regarding the presence or absence of individual imaging criteria. MRI findings in 12 patients with a localized neurofibroma and 40 patients with a neurilemmoma were compared using the chi-square test or Fisher's exact test. RESULTS: MRI findings suggestive of neurofibroma (p < 0.05) were a target sign on T2-weighted images (58% in neurofibromas vs 15% in neurilemmomas), central enhancement (75% vs 8%), and a combination of both findings (63% vs 3%). MRI findings suggestive of a neurilemmoma (p < 0.05) were a fascicular appearance on T2-weighted images (25% vs 63%), a thin hyperintense rim on T2-weighted images (8% vs 58%), a combination of both findings (8% vs 48%), and diffuse enhancement (13% vs 67%). No significant difference was seen between neurofibromas and neurilemmomas for a centrally entering and exiting nerve (42% in neurofibromas vs 23% in neurilemmomas), a peripherally entering and exiting nerve (58% vs 77%), a cystic area (38% vs 64%), a low-signal margin (100% vs 100%), peripheral enhancement (13% vs 26%), or a target sign on contrast-enhanced images (11% vs 31%). CONCLUSION: MRI shows features helpful for differentiating extraaxial neurofibromas from neurilemmomas; however, no single finding or combination of findings allows definitive differentiation.     

Inhibitory effects of Houttuynia cordata water extracts on anaphylactic reaction and mast cell activation

The present study was investigated the effect of Houttuynia cordata THUNB water extract (HCWE) on mast cell-mediated anaphylactic reactions. The mast cell-mediated anaphylactic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. HCWE has been used as a traditional medicine in Korea and is known to have an antioxidant and anti-cancer activities. However, its specific effect of mast cell-mediated anaphylactic reactions is still unknown. We examined whether HCWE could inhibit compound 48/80-induced systemic anaphylaxis, IgE-mediated passive cutaneous anaphylaxis (PCA), and mast cell activation. The oral administration of HCWE inhibited compound 48/80-induced systemic anaphylaxis in mice. HCWE also inhibited the local allergic reaction, PCA, activated by anti-dinitrophenyl (DNP) IgE antibody in rats. HCWE reduced the compound 48/80-induced mast cell degranulation and colchicine-induced deformation of rat peritoneal mast cells (RPMC). Moreover, HCWE dose-dependently inhibited histamine release and calcium uptake of RPMC induced by compound 48/80 or anti-DNP IgE. HCWE increased the level of intracellular cAMP and inhibited significantly the compound 48/80-induced cAMP reduction in RPMC. These results suggest that HCWE may be beneficial in the treatment of mast cell-mediated anaphylactic responses.     

Biochemical changes in dehydrogenase, hydroxylase and tyrosinase of a permethrin-resistant strain of housefly larvae, Musca domestica L

In the present study, a permethrin-resistant strain (ALHF) of housefly was used to understand some enzymic changes in normal biosynthetic pathways after insecticide selection. Aflatoxin B(1) (AFB(1)) as a natural substrate was used to verify the changes on the level of cytochrome P450-dependent monooxygenases and oxido-reductase activities in the ALHF strain compared to an insecticide-susceptible strain, aabys. ALHF yielded three major biotransformation products: aflatoxin B(2a) (AFB(2a)), aflatoxin M(1) (AFM(1)), and aflatoxicol (AFL) by larvae. These principal products were also found in aabys. AFL production rate of ALHF larvae was 5-fold lower than that of aabys. Differences between ALHF larvae and aabys in AFM(1) production were found. ALHF did not differ significantly from aabys in AFB(2a) production. The levels of 17α- and β-hydroxysteroid dehydrogenase (17α- and β-HSD) were also determined to elucidate which type of dehydrogenase activities could be changed. The cytosolic fraction of ALHF larvae yielded about 2-fold higher 17α-estradiol than that of aabys larvae. In contrast, the microsomal fraction of ALHF larvae produced about 2-fold lower amount of 17α-estradiol than that of aabys larvae. The production rate of microsomal fraction of 17β-estradiol ALHF larvae yielded 3-fold lower than that of aabys larvae. Inhibition studies on 17α-HSD and 17β-HSD activities by pyrethroid insecticides showed that there was no inhibition by pyrethroids on the enzyme activity. Therefore, there seems to be no changes on the enzyme structures. Changes on enzyme expression may occur in ALHF larvae in relation to 17α- or β-HSD. To assess biochemical changes of the cuticle formation phenylalanine 4-hydroxylase and tyrosinase activities were determined. The production rate of tyrosine from phenylalanine in ALHF was about 2-fold higher for larvae than that in aabys. l-(dihydroxylphenyl)alanine (DOPA) content was determined in larvae and ALHF possessed 1.6-fold larger amounts of DOPA than aabys. Tyrosinase activity of ALHF larval preparations showed 1.6-fold higher than aabys. In summary, many enzymic changes were found in ALHF strain compared to aabys strain and these changes may be resulted from the permethrin selection.     

In vivo and in vitro immunosuppressive effects of benzo[k]fluoranthene in female Balb/c mice

Although polycyclic aromatic hydrocarbons (PAHs) have been known to suppress immune responses, few studies have addressed the immunotoxicity of benzo[k]fluoranthene (B[k]F). In this study, we investigated the immunosuppression by B[k]F, both in vivo and in vitro, in female BALB/c mice. To assess the effects of B[k]F on humoral immunity as splenic antibody response to sheep red blood cells (SRBCs), B[k]F was given a single dose or once daily for 7 consecutive days po with 30, 60, and 120 micromol/kg. B[k]F reduced the number of antibody-forming cells (AFCs) in a dose-dependent manner. Subacute treatment with B[k]F caused weight increases in liver and decreases in spleen and thymus. The number of AFCs was dramatically decreased by B[k]F in a dose-dependent manner. In a subsequent study, mice were subacutely exposed to the same doses of B[k]F without an immunization with SRBCs, followed by splenic and thymic lymphocyte phenotypings using a flow cytometry and ex vivo mitogen-stimulated proliferation. B[k]F-exposed mice exhibited reduced splenic and thymic cellularity, decreased numbers of total T cells, CD4(+) cells, and CD8(+) cells in spleen, and immature CD4(+)CD8(+) cells, CD4(+)CD8(-) cells, and CD8(+)CD4(-) cells in thymus. The number of CD4(+) IL-2(+) cells was reduced by about 11%, 31%, and 53% following exposure of mice to 30, 60, and 120 micromol/kg of B[k]F, respectively. In the ex vivo lymphocyte proliferation assay, B[k]F inhibited splenocyte proliferation by LPS and Con A. In the in vitro mitogen-stimulated proliferation by untreated splenic suspensions, B[k]F only suppressed splenocyte proliferation to LPS. These results suggested that B[k]F-induced immunosuppression might be mediated, at least in part, through the IL-2 production, and caused by mechanisms associated with metabolic processes.