The gastrointestinal (GI) absorption of orally administered drugs is determined by not only the permeability of GI mucosa but also the transit rate in the GI tract. It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. The reason why the residence time is also a critical factor for drug absorption is that there is the site difference in absorbability for some drugs. We have developed the GI-Transit-Absorption Model (GITA Model) to analyze and predict the drug absorption kinetics by taking into account both the two factors, i.e. GI transit and drug absorbability including its site difference. GITA Model has been already evidenced to be very useful for estimating the absorption kinetics of drugs with various characteristics and applied to assess the human data in combination with the gamma scintigraphy. In this review, the importance of GI transit rate in determining the absorption kinetics and the bioavailability of orally administered drugs is discussed mainly employing GITA Model and the results obtained by the model.

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In this paper, a poly(vinyl chloride) (PVC) membrane electrode is prepared for gemfibrozil, 2, 2-dimethyl-5-(2,5-xylyloxy) valeric acid, based on its ion pair complexes with hexadecyltrioctyl ammonium iodide (HTOA). The membrane composition of the electrode was optimized by using the sequential level elimination method for orthogonal experimental design. The electrode has a Nernstian response range from 2.5×l0⁻⁵ to 0.1 mol/l with an average slope of 55.3 mV/decade. The limit of detection is 7.l×l0⁻⁶ mol/l. The electrode responses were not affected by pH in the range 10.0—12.3. A Na₂B₄O₇–Na₂CO₃ buffer of pH=11.0 was selected as the background electrolyte solution for potentiometric measurements. The electrode was used for determining gemfibrozil in pharmaceutical preparations with satisfactory results.

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Affinity electrophoresis (AEP) using green fluorescent protein (GFP) was studied. We constructed a fusion protein that linked S147PGFP and IgG binding domain C from streptococcal protein G (GFP–SpGC). The affinity of GFP–SpGC for mouse IgG1 was measured. The AEP using GFP does not require a staining step after electrophoresis, and was successful with a non-purified sample. Therefore, this method is simple and useful for measuring many samples such as those used in mutational studies.

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Among the eight inbred mouse strains employed in our preceding report, 12-O-tetradecanoylphorbol 13-acetate (TPA) painting alone induced CD4⁺ regulatory T (Tr) cells in four strains (e.g., C3H/He) at 6—8 weeks of age, but not in the remaining strains (e.g., C57BL/6, BALB/c). In the present study, the effect of growth from 4—14 weeks on delayed-type hypersensitivity (DTH) response was investigated in three inbred murine strains, C3H/He (H-2k), C57BL/6 (H-2b) and BALB/c (H-2d) mice. In all strains older than 10 weeks, DTH response was suppressed exclusively by TPA painting. The defect of suppressive activity for DTH in several of the strains at 6—8 weeks of age was dependent on the presence of cells, which blocked regulatory cell activity at 6—8 weeks of age, but not at 10 weeks of age. The age-dependent difference in regulatory activity was caused by the presence of CD8⁺ contra-regulatory T (Tcr) cells. CD8⁺ contra-regulatory T cells are required to contact regulatory cells in order to block DTH suppressive activity. Adhesion molecules were of great importance in contra-suppression, as antibody treatment to LFA-1 or ICAM-1 blocked this activity. ICAM-1 expression on CD4 T cells greatly increased following growth in 10 week-BALB/c mice receiving TPA than 6-week-old mice, however, a slight increase in growth occurred in 6-to-10-week-old animals in which TPA was absent. The degree of increment in body weight was very similar in these inbred strains. Thymus involution in C3H/He mice was the earliest signal among these mice. This result may suggest that the period of differentiation and maturation of T cells in a first lymphoid tissue for the growth process differs in these three inbred strains. This study provides an interesting example of genetic control of maturation or proliferation of peripheral T cells.

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Protein phosphorylation plays many important roles in cell functions and cell differentiation. To clarify the roles of protein phosphorylation in early embryonic development in mice, 2-cell embryos were cultured in the presence of various protein phosphatase inhibitors such as calyculin A, okadaic acid, cyclosporin A, tacrolimus (FK506) and benzyl-phosphonic acid. Calyculin A potently inhibited the 2-cell cleavage to the 4-cell stage. The concentration for 50% inhibition was 0.26 nM. At the same time, we found that calyculin A-treated 2-cell embryos showed a morula-like shape at a concentration of 2 nM in 24 h. It is well known that E-cadherin plays a key role in the compaction of late 8-cell stage embryos. In this report, we observed the distribution of E-cadherin protein using anti-E-cadherin antibody with a fluorescence microscope, and also evaluated the relative E-cadherin mRNA content at various stages of embryos by RT-PCR and ABI PRISM 7700 System (a real time PCR apparatus). The fluorescence intensity of E-cadherin increased along with the embryonic development. During the embryonic development from the 2-cell stage to the blastocyst stage, the relative E-cadherin mRNA content greatly increased in a time-dependent manner, while the mRNA did not increase with the addition of calyculin A at the 2-cell stage. Therefore, we observed the localization of the E-cadherin protein in calyculin A-treated embryos with a laser microscope. The distribution pattern of E-cadherin was altered by the addition of calyculin A from a scattered pattern throughout the embryos to a localized pattern at the cell-cell boundary region. These results strongly suggest that the distribution of E-cadherin protein is regulated by protein phosphorylation and/or dephosphorylation.

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Effect of nonylphenol on aminopyrine N-demethylase activity, a typical drug-metabolizing enzyme activity, by ten kinds of human hepatic cytochrome P450s (CYP) and on progesterone 17α-hydroxylase activity by steroidogenic CYP17 was investigated. When determined at 2 mM substrate concentration, nonylphenol (1 mM) most efficiently inhibited aminopyrine N-demethylation by CYP2C9 and CYP2C19, by 61% and 59%, respectively, followed by CYP2D6, CYP1A2, CYP2C18 and CYP2C8 (46—51%), whereas inhibition of the activities by other CYPs was less than 27%. Additionally, nonylphenol competitively inhibited diclofenac 4′-hydroxylation by CYP2C9 and S-mephenytoin 4′-hydroxylation by CYP2C19 with K_i values of 5.3 and 37 µM, respectively. Furthermore, nonylphenol exhibited a competitive inhibition of progesterone 17α-hydroxylase activity by CYP17 with K_i value of 62 µM. These results suggest that nonylphenol inhibits human hepatic CYPs, especially CYP2C9 and CYP2C19, and steroidogenic CYP17 activities.

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We examined the expression of mRNAs for inflammatory cytokines and Fas in cultured human fetal membrane cells responding to influenza virus (IV) infection using the reverse transcriptase-polymerase chain reaction (RT-PCR). Primary cultured chorion and amnion cells prepared from human fetal membranes were infected with IV. Chorion cells expressed significant amounts of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-β, IFN-γ and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNAs and small amounts of Fas mRNA in response to IV infection. Amnion cells expressed TNF-α and IFN-β mRNAs in response to IV infection, while expression of the other mRNAs was not altered. We also examined whether or not TNF-α, IFN-β, IFN-γ and Fas participated in IV infection-induced apoptotic DNA fragmentation in chorion cells. Neutralizing antibodies against them did not inhibit DNA fragmentation. These results suggested that chorion cells expressed significant amounts of mRNAs for inflammatory cytokines in response to IV infection, and that, in contrast, mRNA expression was quiescent in amnion cells. Moreover, TNF-α, IFN-β, IFN-γ and Fas do not appear to be directly involved in the apoptosis induction of IV-infected chorion cells. The results indicated that chorion cells may play a role in defense against IV through an antiviral immune response and apoptosis to eliminate own cells and viral pathogens in infected organs, whereas amnion cells do not play such a role.

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It is well known that bronchial asthma is defined as chronic eosinophilic inflammation of the respiratory tract and that as one of the various types of inflammatory cells, eosinophils induce the airway inflammation of chronic asthma. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to play an important role in the prolongation of the survival of eosinophils. We investigated the inhibitory effect of the selective phosphodiesterase (PDE) 4 inhibitors, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]purin-5-one (XT-611) and rolipram, and the nonselective PDE inhibitor theophylline, against GM-CSF-induced prolongation of the survival of eosinophils isolated from patients with bronchial asthma. Eosinophils (10₆ cells/ml) were incubated in the presence of GM-CSF together with or without theophylline, rolipram or XT-611 at 37 °C, and the viable cells were assessed up to 4 d using Trypan blue dye exclusion. The presence of theophylline (10⁻⁴ M), rolipram (10⁻⁴—10⁻⁵ M) or XT-611 (10⁻⁴—10⁻⁵ M) significantly reduced the GM-CSF (10 pg/ml)-induced prolongation of viability of eosinophils. These findings suggest that selective PDE 4 inhibitors, including XT-611, may effectively reduce the activities of inflammatory cells in the airway of bronchial asthma patients.

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Recently, we reported that low molecular weight (LMW) chitosan (chitosan lactate, average MW: 20000) prevents the progression of low dose (100 mg/kg, i.p.) streptozotocin-induced slowly progressive diabetes mellitus in male ICR mice. The present study was designed to clarify the effects of LMW chitosan on hyperglycemia, hyperinsulinemia and hypertriglyceridemia in genetically obese diabetic male KK-A^y mice. LMW chitosan (0.05%, 0.2% or 0.8% water solution) was given daily as drinking water to male KK-A^y mice for 11 weeks, from 5 weeks of age. The non-fasting serum glucose levels of control mice continued to increase slowly throughout the experimental period. LMW chitosan lowered the serum glucose levels in a dose-dependent manner. In these diabetic mice, hyperinsulinemia and hypertriglyceridemia were observed, and LMW chitosan was dose-dependently effective in improving both serum biochemical parameters. LMW chitosan at three doses improved overdrinking and polyuria observed in these diabetic mice. It is concluded from these results that LMW chitosan may be useful for the treatment of obesity-related type 2 diabetes mellitus.

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Dioscin, a saponin extracted from the root of Polygonatum Zanlanscianense Pamp, markedly inhibited proliferation of Hela cells. The results indicated that Hela cells underwent apoptosis in dose- and time-dependent manners when treated with Dioscin. Caspase-3, -8 and -9 activities were also detected. The low enzymatic activity of caspase-8 and high activity of caspase-9 showed that the mitochondrial pathway was activated in apoptosis. The reduced expression of the survival protein Bcl-2 also confirmed this result. These studies may be significant in finding a new drug to treat human cervical cancer.

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We investigated the effects of dietary supplements on atria isolated from male Wistar rats. The examined supplements, which are increasingly used in Japan, those were Ginkgo biloba extract (GBE), catechins, isoflavones, sodium iron chlorophyllin and sodium copper chlorophyllin. GBE at 100—1000 µg/ml significantly increased the beat rate and the contractile force. Catechins at 1—100 µg/ml significantly potentiated the contractile force but did not effect the beat rates. However, isoflavones, sodium iron and sodium copper chlorophyllins did not change the contractile force or the beat rates. To identify the active ingredient of GBE, ginkgolide B, quercetin and amentoflavone on the atria were tested. Ginkgolide B weakened the contractile force. Quercetin potentiated the contractile force at only 30 µg/ml. Amentoflavone significantly increased the beat rate. From these findings, amentoflavone and quercetin were considered to be the principal ingredients of GBE producing the positive chronotropic and inotropic actions, respectively. In the case of catechins, (−)-epigallocatechin gallate (EGCg), one of the principal ingredients, produced inotropic actions. These findings suggest that there are some dietary supplements which affect cardiac function, such GBE and catechins.

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The causal relationship between the inhibition of antibody production and liver injury induced by single doses of acetaminophen (APAP) was investigated in mice. The liver injury and antibody production were evaluated using the serum transaminase activity and the number of antibody forming cells against sheep red blood cells (SRBC), respectively. The relevance of APAP hepatotoxicity with inhibiting antibody production was elucidated in fasted and fed mice treated with a single oral administration of APAP. In fasted mice, the oral administration of APAP produced serious liver injury, while it was not the case in the fed mice. As the antibody production was measured under these conditions, APAP significantly depressed the antibody production in fed mice as well as in fasted mice. The rate of B220 positive cells in the splenocytes was significantly decreased by APAP administration in both the fasted and fed mice. Splenocytes proliferative responses following mitogenic stimulation with concanavalin A or lipopolysaccharide were inhibited by APAP. Moreover, APAP added directly to the splenocyte culture also inhibited the in vitro antibody-producing response to SRBC. These findings indicate that the APAP-induced depression of antibody production may not be a secondary response to APAP-hepatitis, but may be a primary response to APAP.

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7-Isopentenyloxycoumarin (1) was isolated from Heracleum lanatum Michx. (Umbelliferae). Compound 1 inhibited phospholipid metabolism and Epstein–Barr virus activation caused by a potent tumor promoter. In an in vivo experiment, topical application of 1 suppressed skin-tumor-formation induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene (DMBA) initiated mice. And it also suppressed ornithine decarboxylase activity stimulated by TPA on mouse skin. These results indicated that 7-isopentenyloxycoumarin is one of the effective compounds from natural resources for treating skin tumor formation.

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Isoliquiritigenin is a natural pigment with the simple chalcone structure, 4, 2′, 4′-trihydroxychalcone. The effect of this compound on azoxymethane (AOM)-induced colonic aberrant crypt focus and tumor formation in ddY mice was examined. Administration of 15 ppm of isoliquiritigenin in drinking water, significantly suppressed AOM-induced aberrant crypt focus formation (p<0.01), with an inhibitory ratio of 37.3%. Isoliquiritigenin also inhibited AOM-induced colon carcinogenesis by administration in a mixed diet. The average number of tumors was 14.6±8.9 items in the control group and were 7.3±7.3, 3.9±5.6, 4.7±6.5 items in the 10, 100 and 250 ppm in the isoliquiritigenin treated groups, respectively. In histopathological studies, the tumors were identified as adenoma and adenocarcinoma, however, significant differences were not observed between the control group and isoliquiritigenin treated groups. These results indicated that isoliquiritigenin might be a potential chemopreventive agent against colon cancer.

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The aim of the present paper is to study the relation between vasopressin antagonism and the regulation of intraocular pressure (IOP). From the studies on the effect of several vasopressin receptor antagonists, VP-343, OPC-21268, YM087, OPC-31260 and SR121463, on normal IOP and the effect of VP-343 on pupil diameter in rabbit, it was shown that some vasopressin antagonists decreased normal IOP and VP-343 had no influence on pupil diameter. A vasopressin receptor mapping study in normal cynomolgus monkey eye revealed a high density binding site for a [H³]vasopressin V₁ antagonist in the region of iris. These findings suggest that a vasopressin antagonist should decrease normal IOP without miosis and that vasopressin V₁ receptors are present in iris.

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Six flavonoid glycosides, eriocitrin (1), narirutin (2), hesperidin (3), luteolin-7-O-rutinoside (4), isorhoifolin (5), diosmin (6), rosmarinic acid (7) and 5,7-dihydroxycromone-7-O-rutinoside (8), were isolated from the aerial part of Mentha piperita L. Among these compounds, compound 4 showed a potent inhibitory effect on histamine release induced by compound 48/80 and antigen-antibody reaction. This compound was more effective than luteolin and luteolin-7-O-glucoside in inhibiting histamine release from rat peritoneal mast cells. Compound 4 also caused a dose-related inhibition of the antigen-induced nasal response and significant effects were observed at doses of 100 and 300 mg/kg. These results indicate that compound 4 may be clinically useful in alleviating the nasal symptoms of allergic rhinitis.

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Rinbacin is a local Nigerian herbal remedy. The effects of rinbacin on testicular histology were studied in prepubertal rats. Sexually immature male rats, divided into seven per group, were given rinbacin in drinking waters at 0, 26.25 g/l, or 52.50 g/l for 13 weeks, after which the animals were killed and testes excised, weighed, and processed for histologic study. The epididymal sperm number (ESN) was determined. There were no significant effects of either the low or high doses of rinbacin on fluid intake, body weight, testicular weight, and testis-body weight ratio. There was, however, a significant (p<0.05) decrease in the ESN of animals at both doses of rinbacin. Histologic examination of the testes indicated that the high dose of rinbacin induced significant degenerative changes, while the low dose had only a mild effect on testicular histology. Rinbacin decreases the ESN and causes degenerative lesions, especially at the high dose, in prepubertal rats.

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Phthalate esters (PEs), especially di-n-butyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) were detected in various water samples such as river water, well water and tap water. On degradation tests of PEs, Tempaku River water degraded almost 100% of diethyl phthalate (DEP), di-isobutyl phthalate and DBP, and approximately 70% of DEHP. All eight isolates from Tempaku River water (R1—R7, D1) did not degrade dimethyl phthalate (DMP), but showed biodegrading ability for the other PEs. The DBP-degrading ability was particularly high for the isolates R1—R3 and D1 of Acinetobacter lwoffii. Crude enzyme solutions prepared from bacterial cells of these isolates showed a higher degrading activity for DEHP compared with that for microbially-degradable DBP. Particularly high DEHP-degrading activity was found for crude enzyme solutions of the isolate D1. As metabolites from the river water and bacterial isolates, DMP and an unknown diester were produced from DEP. DMP, DEP, monomethyl phthalate, monobutyl phthalate (MBP) and an unknown diester were produced from DBP. DBP, DEP, DMP and an unknown diester were produced from DEHP. As metabolites by the crude enzyme solutions, DMP, MBP and an unknown diester derivative were produced from DBP. DBP, mono-(2-ethylhexyl) phthalate and an unknown diester derivative were produced from DEHP. Diesters with shortened alkyl carbon chains were also found as metabolites by the isolates and their crude enzyme solutions. The results suggest that the alkyl chains in the diesters are also decomposed in addition to monoester formation from DBP or DEHP at the first step reported for animals and some types of bacteria.

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In the present study, a series of 2-(3′-substituted-2′-hydroxypropylamino)pyridines were synthesized and characterized by IR, ¹H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (150, 300 mg/kg) and cardiac activity. 2-(3′-Diethylamino-2′-hydroxypropylamino)pyridine 3 was found to exhibit the highest anticonvulsant activity. 2-(3′-Dimethylamino-2′-hydroxypropylamino)pyridine 2 and 2-[3′-(4″-nitrophenyl-amino)-2′-hydroxypropylamino]pyridine 6 were found to exhibit negative ionotropic activity. 2-(3′-Dimethylamino-2′-hydroxypropylamino)pyridine 2, 2-[3′-(4″-nitrophenylamino)-2′-hydroxypropylamino]pyridine 6 and 2-(3′-piperidino-2′-hydroxypropylamino)pyridine 8 were found to antagonize exhibit β-adrenergic activity.

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The phylogenetic relationship of Cistanche deserticola, C. salsa and C. tubulosa was analyzed by comparing the nucleotide sequences of the plastid rps2 gene and the intergenic spacer region between rpl16 and rpl14. By comparison of sequence data, the Cistanche samples were distinguishable from each other. The results were consistent with their anatomical and chemical characteristics. Intraspecific variations were found in C. salsa and C. tubulosa among the geographical populations. The NJ tree reconstructed based on the sequence data revealed that C. deserticola and C. salsa from China were closely related to each other, and C. tubulosa was placed as an outgroup of them.

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Pancratistatin derivatives, 1-O-(3-hydroxybutyryl)pancratistatin (HBP) and 1-O-(3-O-β-d-glucopyranosylbutyryl)pancratistatin (GBP), showed strong cytostatic activity against rat embryo fibroblast 3Y1 at concentrations less than 1 µM. When the effect on cell cycle progression was examined in 3Y1 fibroblasts arrested at G₀/G₁ phase by serum deprivation, HBP, GBP, and pancratistatin inhibited the progression of 3Y1 fibroblasts from G₀/G₁ to S phase. In addition, when the effect on cell cycle progression was studied in 3Y1 fibroblasts synchronized at late G₁/early S phases by treating with hydroxyurea, HBP blocked further progression through S phase, while GBP and pancratistatin did not affect the progression, but retarded it. On the other hand, when the effect of HBP and GBP on the progression was evaluated in promyelocytic leukemia HL-60RG cells synchronized at G₀/G₁ phase, the cells did not progress into S phase and accumulated in sub G₀/G₁ phase, which indicated apoptotic cells. These findings suggest that of Amaryllidaceae alkaloids, HBP blocks the progression of cell cycle at least at G₀/G₁ and S phases and GBP does at least at G₀/G₁ phase, resulting in apoptosis induction in tumor cells.

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Antipruritic effects of 70% ethanol extract (CM-ext) of Cnidii Monnieri Fructus (dried fruits of Cnidium monnieri Cusson, Umberifferae) were investigated. In mice, an oral administration of CM-ext (200 and 500 mg/kg) inhibited compound 48/80-induced scratching behavior without influence on spontaneous locomotion. Isopimpinellin (3) and osthol (1), coumarin derivatives isolated from CM-ext, showed an inhibitory effect on compound 48/80-induced scratching behavior.

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It is known that expression of endothelin-1 (ET-1) increases in the epidermis after UVB irradiation, and that this plays an important role during the induction of pigmentation both as a mitogen and as a melanogen for normal human melanocytes (NHMC). When ET-1 acts on NHMC via the endothelin B receptor (ET_BR) on their cell surface, mobilization of intracellular calcium is induced, which is followed by activation of Raf-1 located upstream of mitogen activated protein kinase (MAPK). We have continued the search for new agent which inhibit this calcium mobilization and we have found that an extract of Althaea officinalis L. has such an action. In this study, we investigated the precise inhibitory mechanism of this botanical extract on the ET-1-induced activation of melanocytes. Treatment of NHMC with this extract abrogated the stimulatory effect of ET-1 on proliferation and also on activation of MAPK in the intracellular signal transduction pathway, but did not affect the binding of ET-1 to the ET_BR or the production of Inositol 1,4,5-Trisphosphate (IP₃). Further, when this extract was used to treat normal human keratinocytes (NHKC), secretion of ET-1 by those cells was reduced. Taken together, these findings indicate that an extract of A. officinalis inhibits both the secretion of ET-1 from NHKC and the action of ET-1 on NHMC mainly by suppressing the ET-1-induced calcium mobilization without the modification of IP₃ production, which in turn suggests that this extract is a useful ingredient for a whitening agent.

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Salazosulfapyridine (SASP) is widely used orally and rectally in the treatment of ulcerative colitis. SASP is mainly metabolized by hydrolysis and the main active metabolite, 5-aminosalicylic acid (5-ASA), has an antiinflammatory effect. In the present study, we prepared suppositories containing 6.5 mmol of SASP and an enema containing 6.5 mmol of 5-ASA. We measured the concentrations of SASP and its various metabolites, 5-ASA, sulfapyridine (SP), acetylated metabolite of SP (Ac-SP), and N-acetyl-5-ASA (Ac-5-ASA), in the serum and urine after a single administration of each preparation to healthy male volunteers. When the SASP suppository was administered, the maximum concentration (C_max) of SASP and Ac-5-ASA was 2.5±0.4 and 0.5±0.2 µM and the time to C_max (T_max) was 5 and 12 h, respectively. The C_max value of SP, which causes side effects, was one-half of that of the parent compound. No 5-ASA in the serum was observed. When the 5-ASA enema was administered, C_max and T_max values of 5-ASA and Ac-5-ASA were 5.8±2.0 and 13.3±3.6 µM and 1 and 7 h, respectively. The area under the serum concentration–time curve (AUC) of SASP was 27.4±4.8 µM·h, a finding similar to that of 5-ASA after the administration of the 5-ASA enema (29.4±11.1 µM·h). The percentage of urinary recovery of SASP 24 h after administration of the SASP suppository was approximately 0.2%. These results indicate that SASP administered rectally is almost completely hydrolyzed in the colon and that 5-ASA is partially absorbed from the small intestine in unchanged form. On the other hand, approximately 0.3% of 5-ASA was recovered in the urine in unchanged form after the administration of the 5-ASA enema, whereas the urinary recovery of Ac-5-ASA was more than 10%. The present findings suggest that 5-ASA has favorable absorptive properties and can be expected to have systemic action after rectal administration of a 5-ASA enema.

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Chitosan (CS) gel beads were prepared in 10% amino acid solution (pH 9) and modified by forming an electrostatic complex between the amino group of CS and the carboxyl group of chondroitin sulfate (Cho). Modification of the CS gel matrix by Cho inhibited the in vitro release of prednisolone (PS) from the gel beads. CS gel beads modified by Cho (CS-Cho) were implanted into air pouches (AP) prepared subcutaneously on the dorsal surfaces of mice. No inflammatory response was observed. The in vivo release of PS from CS-Cho gel beads and their biodegradation in the AP was slower than beads without Cho treatment. After 28 days of implantation, CS-Cho gel beads (deacetylation of CS: 90%) were still detectable, although they had become softer and smaller. Modification of the CS gel matrix by Cho controls the biodegradation of the beads and the release of the drug. This effect makes these beads a promising biocompatible and biodegradable vehicle for sustained drug delivery.

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A preliminary screening for the inhibitory effects on the activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by applying AhR-based bioassays for dioxins, the Ah-Immunoassay and CALUX assay, was attempted. Thirty-nine food extracts including vegetables, fruits, herbs, and teas were initially screened in vitro. We first examined the application of both bioassay methods using green tea extracts and (−)-epigallocatechin gallate, reported antagonists of the AhR, since the results could reveal an inhibitory effect versus the control in both assays. Food extracts were then tested. Among the herbs, extracts of sage, among the vegetables, green leafy ones such as spinach, and among the fruit, citrus showed inhibitory effects on AhR activation by TCDD, although some tested samples did not show parallel behavior in both assays. Sage had a remarkable inhibitory effect (79% in the CALUX assay and 83% in the Ah-Immunoassay compared with control) and its effects were dose dependent. The results suggest that these assays might be applicable to the preliminary screening of antagonist activity against the AhR. Moreover, based on these results, the potential benefit of factors that function as dietary ligands of the AhR and are present in several foodstuffs is indicated.

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