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Cycloaddition catalyzed by transition metals such as rhodium (I) is an important way to synthesize functionalized molecules in medicinal chemistry. When the reagent has a saturated ring containing more than five carbons (or heavy atoms), the reaction can progress when the compound has an allenyl group, but not for a vinyl group. Here, we constructed two computational models for allenylcyclopentane-alkyne and vinylcyclopentane-alkyne, and obtained their reaction pathways using density functional theory (DFT). From the reaction pathways, we confirmed that the former model has a much lower reaction energy than the latter. We also found that the molecular orbitals of the transition state structure at the rate-controlling step contribute significantly to the difference in reactivity between the two models.

Paclitaxel and nanoparticle albumin-bound paclitaxel are known to cause adverse events of eye disorders, such as cystoid macular edema. However, at present, the risk factors remain unclear. Therefore, risk factors for eye disorders caused by paclitaxel and nanoparticle albumin-bound paclitaxel were studied. This retrospective study targeted patients who were newly administered paclitaxel or nanoparticle albumin-bound paclitaxel at Kyoto Okamoto Memorial Hospital between April 1, 2012, and March 31, 2017. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. To analyze the risk factors, logistic regression analysis using 41 factors was performed. Of 128 subjects, 13 (10.2%) had eye disorders with symptom degrees of Grades 1 and 2. The symptoms were conjunctivitis or subconjunctival hemorrhage (3.1%), visual acuity reduction (2.3%), blurred vision and eye pain (1.6% each), eye mucus, blepharitis, stye, watering eyes, photopsia, and muscae volitantes (0.8% each). In eight patients, the conditions patients improved with spontaneously or with medication use; no improvements were observed the cases of visual acuity reduction, blurred vision, or muscae volitantes. Multivariate logistic regression analysis revealed that a cumulative dose of ≥819 mg/m 2 (odds ratio: 5.34, 95% confidence interval: 1.32-21.60, p=0.019) and baseline alkaline phosphatase ≥256 U/L (odds ratio: 3.74, 95% confidence interval: 1.02-13.70, p=0.046) were significant risk factors associated with eye disorders. In conclusion, it was determined that paclitaxel- and nanoparticle albumin-bound paclitaxel-related eye disorders might be influenced by cumulative dose and baseline alkaline phosphatase.

Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.

Different monounsaturated fatty acid (MUFA) species have distinct pathophysiological activities. cis-Palmitoleic acid (16:1n-7) was previously reported to improve insulin sensitivity in animal studies. The proportions of hepatic MUFAs are generally considered to reflect changes in the activities of fatty acid modifications (∆9 desaturation and fatty acid elongation). However, hepatic levels of 16:1n-7 are markedly lower than those of oleic acid (18:1n-9). Nevertheless, no convincing explanation has yet been provided for the low level of 16:1n-7. We hypothesized that fatty acid degradation plays a key role in maintaining a low 16:1n-7 proportion in the liver. In order to corroborate the link between β-oxidation and the proportion of 16:1n-7, rats were fed a control diet, fed a fat-free diet to up-regulate fatty acid modifications, but not β-oxidation, or treated with clofibric acid to up-regulate fatty acid modifications and β-oxidation. The nutritional manipulation markedly increased the proportions of 16:1n-7, 18:1n-9, and cis-vaccenic acid (18:1n-7). Although the pharmacological manipulation enhanced fatty acid modifications to largely the same extent as the nutritional manipulation and markedly elevated the proportion of 18:1n-9, those of 16:1n-7 and 18:1n-7 remained largely unchanged. The oxidation rates of 16:1n-7, 18:1n-9, and 18:1n-7 in liver slices were in the following order: 16:1n-7>18:1n-7≑18:1n-9 in control livers, and were increased by the pharmacological manipulation and decreased by the nutritional manipulation. These results strongly suggest that β-oxidation, in concert with fatty acid modifications, plays a key role in regulating the MUFA profile and is crucially involved in maintaining low 16:1n-7 levels in the liver.

We discovered that a reagent comprising a combination of PhBCl2 and nitriles was useful for syntheses of both 3-acylindoles and 1-(1H-indol-3-yl)alkylamine from indoles. The reaction proceeded selectively at the 3-position of indoles providing 3-acylindoles in moderate to high yields on treatment with the above reagent. Furthermore, the reaction provided the corresponding amine products in moderate to high yields after the intermediate imine was reduced by NaBH3CN. These reactions proceeded under mild conditions and are applicable to the formation of indoles functionalized at the 3-position.

Fibrates are used in biochemical and pharmacological studies as bioactive tools. Nevertheless, most studies have lacked information concerning the concentrations of fibric acids working inside tissues because a simple and sensitive method is not available for their quantitation. This study aimed to develop a simple and sensitive bioanalytical method for the quantitation of clofibric, bezafibric and fenofibric acids in samples of very small portions of tissues. Fibric acids were extracted into n-hexane-ethyl acetate from tissue homogenates (10 mg of liver, kidney or muscle) or serum (100 µL) and were derivatized with 4-bromomethyl-6,7-dimethoxycoumarin, followed by HPLC with fluorescence detection. These compounds were separated isocratically on a reversed phase with acetonitrile-water. Standard analytical curves were linear over the concentration range of 0.2-20 nmol/10 mg of liver. Precision and accuracy were within acceptable limits. Recovery from liver homogenates ranged from 93.03 to 112.29%. This method enabled the quantitation of fibric acids in 10 mg of liver from rats treated with clofibric acid, bezafibric acid or fenofibrate. From these analytical data, it became clear that there was no large difference in ratio of acyl-CoA oxidase 1 (Acox1) mRNA level to fibric acid content in the liver among the three fibric acids, suggesting that these three fibric acids have similar potency to increase expression of the Acox1 gene, which is a target of peroxisome proliferator-activated receptor α. Thus, the proposed method is a simple, sensitive and reliable tool for the quantitation of fibric acids working in vivo inside livers.

The bursa of Fabricius (BF) is a unique primary lymphoid organ, and among vertebrates is unique to birds. Despite its importance to the immune systems of various avian species, little is known of the molecular mechanisms underlying early BF development. In the present study, we demonstrated that apoptosis occurs during early development of the bursa of Fabricius in chicken embryos. Initial histological analyses of BF morphogenesis in chicken embryos led to the hypothesis that formation of the bursal lumen correlates with fusion of vacuoles, which appear in the cloacal epithelial bud. Using terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) analysis and immunostaining with an anti-cleaved (activated) caspase-3 antibody, we detected multiple apoptotic cells around these vacuoles. In further experiments, treatments with a caspase inhibitor caused abnormal bursal lumen in vivo. The present data indicate that apoptosis may play important roles in BF morphogenesis in chickens.

The genome of the facultative anaerobic thermoacidophilic archaeon Thermoplasma volcanium contains the open-reading frames (ORFs) tvsod and tvogg, which are predicted to encode a putative superoxide dismutase and an 8-oxoguanine DNA glycosylase, respectively. Tvsod is immediately upstream of tvogg, and these two ORFs are aligned in a head-to-tail manner in a single operon. A previous study showed that T. volcanium contains an ORF (TVN0292) encoding the ferric uptake regulator (Fur) and that the T. volcanium Fur protein (TvFur) binds to its own promoter in a metal-dependent manner in vitro. Here, we demonstrated that TvFur also binds to the tvsod-tvogg promoter and determined the TvFur-binding sequences in the tvsod-tvogg promoter by DNaseI footprinting analysis. These results suggest that Fur is required for resistance against reactive oxygen species in this facultative anaerobic archaeon.

Quetiapine, an antipsychotic drug used for schizophrenia treatment, is poorly water soluble, and therefore, administration of the more water-soluble quetiapine fumarate is preferred. Absorption of quetiapine through biological membranes may be improved by enhancing the solubility of the quetiapine base, the non-ionic form. In this study, the currently used salt form was converted into the free base (oily material). We employed cyclodextrins (CDs) as pharmaceutical additives to improve the solubility of the quetiapine base. The formation of quetiapine-β-cyclodextrin (β-CD) complexes was studied by phase solubility studies, continuous variation method, NMR spectroscopy, and powder X-ray diffraction. The formation of a poorly water-soluble complex was confirmed by the phase solubility study, and the interaction between quetiapine and β-CD in water was confirmed by NMR spectroscopy. In addition, the effects of β-CD derivatives (glucosyl-β-CD, maltosyl-β-CD, 2-hydroxypropyl-β-CD, dimethyl-β-CD, and trimethyl-β-CD) on the solubility of the quetiapine base were studied. The findings indicated that the aforementioned hydrophilic β-CD derivatives could be used as pharmaceutical additives of quetiapine for parenteral formulations as a result of the improved solubility of the quetiapine base because of inclusion complexation. Therefore, converting the currently used salt form into the free base, investigating the free base as a candidate for CD inclusion, and converting the oily material such as the free base into a powder by forming an inclusion complex that is easy to deal with is considered a worthwhile approach that may lead to novel formulations of the drug in question.

The administration of fibrates (fenofibrate, bezafibrate and clofibric acid) to rats induced stearoyl-CoA desaturase (SCD) in the liver, and increased relative expression of mRNAs encoding SCD1 and SCD2 in dose- and time-dependent manners. The magnitudes of the increases in SCD2 mRNA level caused by fenofibrate and clofibric acid were much higher than those of SCD1 at relatively higher doses of the fibrates, and a relatively long time (7 or 14 d) was required for significant induction of SCD2 mRNA expression compared with that of SCD1. Although the absolute number of transcripts for SCD2 was 1,800 times lower than that of SCD1 in the control liver, it was strikingly increased by fibrates. These results suggest that differential regulations operate for the gene expression between SCD1 and SCD2, and that the physiological significance of SCD2 is distinct from that of SCD1 in the liver.

The fatty acid profile of hepatic lipid in spontaneously hypertensive rats (SHR)/NDmcr-cp (cp/cp) rats (SHR/NDcp), which offer an animal model of the metabolic syndrome, was characterized by comparing those in Wistar Kyoto rats (WKY), SHR, stroke-prone spontaneously hypertensive rats (SHRSP) and SHR/NDmcr-cp (+/+) rats (SHR/ND+) . Hierarchical clustering analysis revealed that SHR/NDcp and the other four strains and/or substrains of rats were clearly disparate in fatty acid profile of hepatic lipid and that the disparity observed was due to the drastic increases in the mass of monounsaturated fatty acids, especially palmitoleic acid and oleic acid, in the liver of SHR/NDcp. Activities of stearoyl-CoA desaturase (SCD) and palmitoyl-CoA chain elongase in hepatic microsomes of SHR/NDcp were markedly higher than those of WKY, SHR, SHRSP and SHR/ND+. Activities of palmitoleoyl-CoA chain elongase in the liver of SHR/NDcp were also higher, but to a lesser extent. mRNA levels of SCD1 and elongation of very long-chain fatty acids (Elovl6), but not Elovl5, in the liver of SHR/NDcp were remarkably higher than those of the other four groups of rats. These results suggest that the enhanced expressions of SCD1 and Elovl6 induced abnormalities in fatty acid profile in the liver of SHR/NDcp.

The effect of fibrates (clofibric acid, bezafibrate and fenofibrate) on the gene expression and activity of 1-acylglycerophosphocholine acyltransferase (LPCAT) was investigated. The administration of 0.1% (w/w) clofibric acid, bezafibrate or fenofibrate in diet for 14 d to rats induced LPCAT activity in hepatic microsomes in the following order: fenofibrate>bezafibrate>clofibric acid. The LPCAT induced by fenofibrate preferred to arachidonoyl-CoA and linoleoyl-CoA to a greater extent than did LPCAT in control microsomes. The treatment with the fibrates resulted in upregulation of the relative expression of mRNAs encoding LPCAT3 and LPCAT4 in the following order: fenofibrate>bezafibrate>clofibric acid. The administration of fibrates did not change the expression of genes encoding either LPCAT1 or LPCAT2. The treatment with fibrates elevated relative levels of both mRNAs encoding Δ6 desaturase (Fads2) and Δ5 desaturase (Fads1) in the order of fenofibrate>bezafibrate>clofibric acid, and the extent of the increase in the level of Δ6 desaturase mRNA was greater than that of Δ5 desaturase. Fatty acid profile in hepatic phosphatidylcholine (PC) was significantly changed by the treatments with fibrates. These results suggest (i) that fibrates induce LPCAT activity in hepatic microsomes by elevating the expression of genes encoding LPCAT3 and LPCAT4, (ii) that the changes in fatty acid profile of hepatic PC are, in part, due to the elevated expression of two isoforms, LPCAT3 and LPCAT4, and (iii) that the ability of fibrates to induce these changes are in the order of fenofibrate>bezafibrate>clofibric acid.

The gastrointestinal transition of mucoadhesive drug carriers may be affected by food intake, since food changes the physiological conditions of the gastrointestinal tract, and the food content itself is a physical obstruction for the drug carriers. Here we investigated the effects of food intake on the gastrointestinal transition and mucoadhesive function of submicron-sized chitosan-coated liposomes (ssCS-Lip). The stomach and small intestine were removed after oral administration of ssCS-Lip and non-coated liposomes (ssLip) containing fluorescent dye to fasted or fed rats, and retentive properties were quantitatively confirmed by measuring the amount of dye in each part of the gastrointestinal tract. Both types of liposome were retained in the stomach at approx. 40% in the fed rats at 1 h after oral administration, whereas transitions in the intestine were reduced compared to the fasted rats. However, the transition of ssCS-Lip in intestine was prolonged compared to ssLip even, in the fed state. The mucoadhesive behavior of ssCS-Lip was evaluated by confocal laser scanning microscopy. The ssCS-Lip tended to penetrate into the mucosal part of the intestine, and in addition, ssCS-Lip was detected in the basolateral side in both conditions, and therefore the mucopenetrative function was confirmed in the fed condition. Based on these results, we confirmed that ssCS-Lip shows a predominant gastrointestinal transition and mucopenetration, even after food intake.

This study sought to evaluate the in vitro transfection efficiency of plasmid DNA (pDNA)-loaded chitosan-modified poly(DL-lactide-co-glycolide) nanospheres (CS-PLGA NS) in a gene-delivery system. Using the emulsion solvent diffusion (ESD) method, pDNA-loaded PLGA NS was prepared and the surface of the PLGA NS was modified by binding to CS. Gene transfection ability of CS-PLGA NS was examined in A549 cells. The luciferase gene was used as a reporter gene. The pattern of luciferase activity by pDNA-loaded CS-PLGA NS was initially weak, but gradually grew stronger before decreasing activity. These phenomena should be in accordance with the sustained-release profile of pDNA from PLGA NS in the cytosol and the pDNA protection against DNase. Positively charged CS-PLGA NS was found, by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, not to exhibit cytotoxicity on A549 cells. These results suggest that CS-PLGA NS are potential contributors to efficient pDNA delivery due to their increased interactions with cells and lack of cytotoxic effects.

Alterations by perfluorinated fatty acids (PFCAs) with a chain length of 6-9 carbons in the fatty acid profile of hepatic lipids of mice were investigated. The characteristic changes caused by all the PFCAs examined were increases in the contents and proportions of oleic acid (18 : 1), palmitoleic acid (16 : 1) and 8,11,14-eicosatrienoic acid (20 : 3) in hepatic lipids. Hepatic contents of palmitic acid were also increased by the treatments with the PFCAs. These effects were almost dependent on the hepatic concentrations of PFCA molecules regardless of their carbon chain length. Perfluorooctanoic acid elevated the expressions of mRNA encoding acetyl-CoA carboxylase, fatty acid synthase, malic enzyme, stearoyl-CoA desaturase (SCD) (SCD1 and 2), chain elongase (ELOVL5), Δ6 desaturase (Fads2), 1-acylglycerophosphocholine acyltransferase (LPCAT) (LPCAT3). The four PFCAs examined induced microsomal SCD and LPCAT in hepatic concentration-dependent manners regardless of carbon chain length. One linear regression line was confirmed between LPCAT activity and hepatic concentration of PFCA at wide range of the concentration, whereas the induction of SCD was saturable at relatively low concentration of PFCAs. These results suggest (i) that PFCAs with a chain length of 6-9 carbons change the fatty acid profile of hepatic lipids by increasing contents and proportions of 16 : 1, 18 : 1 and 20 : 3, (ii) that these alterations in fatty acid profile are caused by up-regulation of SCD, de novo fatty acid synthesis, chain elongase and Δ6 desaturase and (iii) that the mechanism underlying SCD induction is, in part, mediated through peroxisome proliferator-activated receptor α.

Treatment composed of a gastric mucoadhesive antibiotic with slow release drug delivery is expected to be effective for the eradication of Helicobacter pylori (H. pylori). In this study, we evaluated the slow release property of the tetracycline-sucralfate acidic complex. Tetracycline was the antibiotic selected because of its complexation capacity with sucralfate. Sustained release was tested using two different dissolution test methods: paddle and flow-through cell. The adhesive paste formed from the acidic complex displayed a longer sustained release profile of tetracycline using flow-through cell method. The milder conditions of the flow-through cell method better mimicked the fasted state of the stomach, suggesting that the oral administration with fasting is appropriate for the acidic complex. Furthermore, the paste formation protected the tetracycline from decomposition under an acidic condition, which apparently contributes to long-term release. Change in the zeta potential of the acidic complex particles was helpful in clarifying the release mechanisms of the tetracycline. The data indicated that the immediate release of tetracycline in the early stage of the test was indispensable to the subsequent paste formation that enables slow release. If administrated orally with fasting, the acidic complex rapidly adheres to the gastric mucosa and sustains long-term release of the tetracycline to the gastric lumen or mucus layer. This antibiotic delivery mechanism, which requires only a minimum dosage, may be effective for efficient eradication of H. pylori.

Effects of supplemented docosahexaenoic acid (DHA), given as diacylglycerol (DG) rich in DHA (DHA-DG), triacylglycerol (TG) rich in DHA (DHA-TG) or fish oil concentrate (DHA-70), on the serum concentration of TG and its bioavailability in the rats with diet-induced hyperlipidemia were studied. Hypertriglyceridemia was induced by feeding male Wistar rats a semi-purified diet that contained 5% corn oil and 50% sucrose by weight. In addition to the feeding of dietary corn oil, the rats received DHA intragastrically at a dose of 500 mg/kg body weight once a day for 28 d and the control rats were given olive oil. The serum concentration of TG in the rats that received DHA-DG was significantly lower than in the control rats. However, there were no significant differences in diet intake, energy intake, body weight gain, visceral fat mass or fecal excretion of total fatty acids among the four groups. The amounts of DHA excreted into the feces of the three groups of rats that received DHA were approximately 0.4% of the DHA administered. The extent of the decreases induced by DHA-DG in the serum level of TG was almost the same as those induced by DHA-TG and DHA-70. The administration of DHA, regardless of the differences in molecular structure, did not affect the hepatic contents of TG or phospholipid. The administration of DHA-DG considerably increased the proportions of DHA and eicosapentaenoic acid (EPA) while decreasing the proportion of arachidonic acid in hepatic lipids, and as a result in the lipids in serum and erythrocytes, to the same extents as did DHA-TG and DHA-70. These results suggest that the hypotriglyceridemic effects and bioavailability of DHA when supplemented in the form of DG are essentially equivalent to those of DHA-TG and DHA-70.

In the course of the investigation of effects of newly synthesized matrix metalloproteinase inhibitors (MMPIs), FYK-1388, FYK-1352 and F61-1008, which have strong and broad matrix metalloproteinase (MMP) inhibitory activity, on wound healing in streptozotocin (STZ)-induced diabetic rats, strong reducing effects on serum triacylglycerol (TG) have been found. Namely, when examined using breaking wound strength as an index, MMPIs did not significantly facilitate wound healing in STZ-induced diabetic rats. Unexpectedly, however, the treatment of STZ-induced diabetic rats with MMPIs markedly lowered the serum level of TG without changing the blood glucose level. Among these compounds tested, FYK-1388 was the most effective, and the compound reduced serum concentrations of TG and cholesterol and levels of very low-density lipoprotein (VLDL)-TG and low density lipoprotein (LDL)-cholesterol in a dose-dependent manner. FYK-1388 did not affect serum levels of free fatty acids, high-density lipoprotein (HDL)-cholesterol, aspartate aminotransferase and alanine aminotransferase, mass of body fat, liver weights, and hepatic contents of TG and cholesterol. Moreover, treatment of Zucker fa/fa rats with FYK-1388 lowered serum levels of TG and cholesterol without changing blood levels of glucose and insulin. Since the structures of these MMPIs markedly differ from those of the hypotriglyceridemic drugs that are used clinically, it seems plausible that these MMPIs could be used as a new type of hypotriglyceridemic drug.

Fate of perfluorooctanoic acid (PFOA) after an intravenous injection to male rats at the dose of 0.041 mg/kg body weight was compared with that at the dose of 16.56 mg/kg body weight. In the liver, 52% and 27% of PFOA dosed was recovered 2 h after an intravenous injection at the low and the high doses, respectively. By contrast, larger proportion of PFOA dosed was distributed to serum, other tissues and carcass at the high dose compared with the low dose. Subcellular distribution of PFOA was determined in the liver. At the dose of 0.041 mg/kg, 45%, 34%, 18% and 3% were distributed to 8000 g pellet, 18000g pellet, 105000g pellet and 105000g supernatant fraction, respectively; 28%, 17%, 13% and 43% of PFOA were distributed to these fractions, respectively, at the dose of 16.56 mg/kg. The higher the concentration of hepatic PFOA was, the more the PFOA was distributed to 105000g supernatant fraction. Biliary excretion index increased as PFOA concentration raised in the liver. These results suggest that PFOA is preferentially taken-up by the liver, and distributed to membrane fractions, especially 18000g pellet, and hardly excreted into bile when exposed at very low dose.

The potency of the induction of hepatomegaly, peroxisomal beta-oxidation and microsomal 1-acylglycerophoshocholine (1-acyl-GPC) acyltransferase was compared among perfluorinated fatty acids (PFCAs) with 6-9 carbon chain length in the liver of male and female mice. All PFCAs examined induced hepatomegaly and peroxisomal beta-oxidation and the potency was in the order of perfluorononanonic acid (PFNA), perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHA) and perfluorohexanoic acid (PFHeA) when compared with the relative doses to induce the two parameters. Microsomal 1-acyl-GPC acyltransferase was induced by PFHA, PFOA and PFNA, as was peroxisomal beta-oxidation. No significant sex-related difference was observed in the induction of peroxisomal beta-oxidation by any PFCAs examined. PFNA and PFOA accumulated in the liver of both male and female mice in a dose-dependent manner. PFHA accumulated in the liver to a lesser extent; little PFHeA accumulated in the liver. Hepatic concentrations of PFNA, PFOA and PFHA were higher in male mice than those in female mice. One linear regression line was confirmed between the activities of peroxisomal beta-oxidation and hepatic concentrations of PFHeA, PFHA, PFOA and PFNA in male mice regardless of their carbon chain lengths, and the activities were saturable at the concentrations over approximately 500 nmol/g liver. Similar linear regression line was obtained between the two parameters in female mice. These results suggest (i) that the longer the perfluoroalkyl chain becomes, the more PFCA accumulates in the liver of both male and female mice, (ii) that the accumulated PFCAs induce hepatomegaly, peroxisomal beta-oxidation and microsomal 1-acyl-GPC acyltransferase, and (iii) that the difference observed in the accumulation of PFHA, PFOA and PFNA in the liver between male and female mice is not enough to produce obvious sex-related difference in the induction of peroxisomal beta-oxidation.

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.

Effects of 8-2 fluorotelomer alcohol on fatty acid composition of lipid in the liver of rats were investigated. Feeding of male rats with a diet that contained 8-2 fluorotelomer alcohol at concentrations of 0.2, 0.4 and 0.8% (w/w) for 14 d caused a significant increase in proportion and content of oleic acid (18 : 1 (n-9)) in the liver. The treatment of rats with 8-2 fluorotelomer alcohol increased activities of palmitoyl-CoA chain elongase (PCE) and stearoyl-CoA desaturase (SCD) and mRNA expressions for rat fatty acid elongase 2 (rELO2) and stearoyl-CoA desaturase 1 (SCD1), but neither rat fatty acid elongase 1 (rELO1) or stearoyl-CoA desaturase 2 (SCD2), in the liver in dose-dependent manners. Multiple regression analyses, which were performed to estimate relative contribution of PCE and SCD for determination of the proportion or the content of 18 : 1 (n-9), revealed that the three parameters were significantly correlated and that standardized partial regression coefficient of PCE was higher than that of SCD. These results suggest that 8-2 fluorotelomer alcohol caused considerable changes in the composition and the content of fatty acid, especially 18 : 1 (n-9), in the liver by inducing PCE and SCD, and that PCE plays a crucial role in the increased proportion of 18 : 1 (n-9) in the liver of the rats given fluorotelomer alcohol.

We attempted to make the rapidly dissolving tablet (Tab) containing solid dispersion particles (SD) with indomethacin (IMC) and porous silica (Sylysia350) as carrier prepared by using spray-drying technique. Rapidly dissolving tablet was formulated with mannitol as a diluent and low substituted hydroxypropylcellulose (L-HPC) or partly pre-gelatinized starch (PCS) as a disintegrant. The percent dissolved from Tab (SD) was higher than that of tablet containing physical mixture (PM) at 20 min. Nearly 100% of drug in Tab (SD) was dissolved within 60 min, while the drug dissolution of Tab (PM) was not completed at the same time period. In addition, the tensile strength of Tab (SD) was much higher than that of Tab (PM). Adding L-HPC in Tab (SD) (Tab (SD-L-HPC)), the percent dissolved from Tab (SD-L-HPC) at 5 min became much higher than that from Tab (SD). The dissolution profile of IMC from Tab (SD-L-HPC) was almost the same irrespective of the compression pressure, while the tensile strength of tablet increased with increasing the compression pressure. In comparing the compaction property of these tablets by observing the ratio of residual die wall pressure (RDP) to maximum die wall pressure (MDP) (RDP/MDP), it was found that addition of L-HPC in the tablet formulation improved compactibility. In case that PCS was formulated as disintegrant, Tab (SD-PCS), similar improvement in the dissolution profile and tensile strength was observed, though the dissolution rate of IMC from Tab (SD-PCS) was slightly lower than that from Tab (SD-L-HPC) irrespective of the compression pressure.

The effects of the contents of aminoalkyl methacrylate copolymer E (AMCE) in a wax matrix on the mechanism of polymorphic transformation of glyceryl monostearate (GM) were clarified by evaluating the enthalpy change defined as 1.51 (DeltaH(1)-DeltaH(2))/DeltaH(2), where DeltaH(1) and DeltaH(2) denote the enthalpies in the first and second thermal analyses, respectively. Using this value, K(1), the rate constant of transformation from alpha-form to beta'-form, and K(2), the rate constant of transformation from beta'-form to beta-form, could be obtained. As the ratio of AMCE increased, K(2) increased, but a minimum point existed for K(1). K(1) was always larger than K(2), but gradually approached K(2) as the ratio of AMCE increased. The optimum temperature for the transformation of GM was 50 degrees C, at which the enthalpy change was maximum. To prepare the wax matrix preparation of clarithromycin (CAM), we considered 40 degrees C the optimum treatment temperature for the transformation of GM in a CAM wax matrix compounded from CAM, GM and AMCE, since the matrices were mutually welded at above 45 degrees C during the spray congealing process. Although K(1) and K(2) were almost the same at 40 degrees C, the rate of transformation was accelerated by tumbling. By applying the tumbling that accelerated the transformation of GM in a CAM wax matrix, almost all of the alpha-form disappeared, and the release of CAM from the wax matrix diminished when the enthalpy change was more than 0.8.

The potency to accumulate triglyceride (TG) was compared between perfluorinated fatty acids (PFCAs) with different carbon chain lengths in the liver of male and female rats and induction of peroxisomal beta-oxidation. In male rats, either perfluoroheptanoic acid (C7) or perfluorooctanoic acid (C8) had no effect, although perfluorononanonic acid (C9) and perfluorodecanoic acid (C10) markedly accumulated TG. In female rats, C7, C8, and C9 did not cause TG accumulation, whereas C10 caused TG accumulation at the same level as in male rats. TG accumulation induced by C9 was regulated by the level of testosterone in male rats. In contrast with TG accumulation, peroxisomal beta-oxidation was induced by C8, C9, and C10 in male rats and by C9 and C10 in female rats. Only a slight difference was observed in the induction by C9 between male and female rats. The induction of TG accumulation by these PFCAs occurred in a dose-dependent manner and significantly correlated with hepatic concentrations of PFCA regardless of their carbon chain length, as was observed with induction of peroxisomal beta-oxidation. There is, however, a striking difference in the hepatic concentration of PFCA required to cause induction of TG accumulation and that of peroxisomal beta-oxidation. The concentration of PFCA required to induce TG accumulation is much higher than that to induce peroxisomal beta-oxidation. These results strongly suggest that TG accumulation induced by PFCAs, as well as the induction of peroxisomal beta-oxidation, is dependent only on the number of PFCA molecules in hepatocytes, but is not due to the difference in their chemical structures, and that there is a marked difference in the PFCA threshold to cause distinct biological effects.

The purpose of this study was to clarify the mechanism of transformation from alpha-form to beta-form via beta'-form of glyceryl monostearate (GM) and to determine the optimum conditions of heat-treatment for physically stabilizing GM in a pharmaceutical formulation. Thermal analysis repeated twice using a differential scanning calorimeter (DSC) were performed on mixtures of two crystal forms. In the first run (enthalpy of melting: DeltaH1), two endothermic peaks of alpha-form and beta-form were observed. However, in the second run (enthalpy of melting: DeltaH2), only the endothermic peak of the alpha-form was observed. From a strong correlation observed between the beta-form content in the mixture of alpha-form and beta-form and the enthalpy change, (DeltaH1-DeltaH2)/DeltaH2, beta-form content was expressed as a function of the enthalpy change. Using this relation, the stable beta-form content during the heat-treatment could be determined, and the maximum beta-form content was obtained when the heat-treatment was carried out at 50 degrees C. An inflection point existed in the time course of transformation of alpha-form to beta-form. It was assumed that almost all of alpha-form transformed to beta'-form at this point, and that subsequently only transformation from beta'-form to beta-form occurred. Based on this aspect, the transformation rate equations were derived as consecutive reaction. Experimental data coincided well with the theoretical curve. In conclusion, GM was transformed in the consecutive reaction, and 50 degrees C was the optimum heat-treatment temperature for transforming GM from the alpha-form to the stable beta-form.

The degree of bitterness of clarithromycin (CAM) dry syrup was evaluated using several methods. Using the inversion method, shaking method, and paddle method, a reasonable correlation between the bitter taste and the amount dissolved was not observed. A mini-column with inner diameter of 0.76 cm and height of 5 cm packed with CAM dry syrup was used for the release test. The release rate of CAM in test solution, which passed through the mini-column, was then measured to evaluate bitterness. The release rate of CAM in the release test using the mini-column correlated well with the results of a sensory test for the bitterness of CAM dry syrup. The dissolution rate constant, defined as the percentage of CAM dissolved from the unit void surface multiplied by the void volume, was inversely proportional to the linear velocity of the test solution. The critical factors affecting evaluation of bitterness were the void volume of the column and linear velocity of the test solution. The optimum linear velocity and void volume were 0.048-0.021 cm/min and 0.27-0.12 cm3, respectively. In addition, the threshold of bitterness of CAM dry syrup was defined as the concentration at which half of the volunteers recognized bitterness in the sensory test. This threshold was found to be 135 microg/ml using the mini-column.

The purpose of this study was to reveal the effectiveness of the polymer coated liposomes as a carrier of the anticancer drug doxorubicin in intravenous administration. The size controlled doxorubicin-loaded liposomes (egg phosphatidylcholine : cholesterol = 1:1 in molar ratio) were coated with hydrophilic polymers (polyvinyl alcohol; PVA and hydroxypropylmethylcellulose; HPMC) having a hydrophobic moiety in the molecules (PVA-R, HPMC-R). The existence of a thick polymer layer on the surface of the polymer coated liposomes was confirmed by measuring the change in particle size and the amount of polymer on the liposomal surface. The polymer coating effects on the tumor accumulation of the drug encapsulated in the liposomes were evaluated in Walker rat carcinoma 256 cell bearing rats. The doxorubicin-loaded liposomes coated with PVA-R and HPMC-R showed higher drug accumulation into the tumor site by prolonging the systemic circulation in tumor-bearing rats. The targeting efficiency of the polymer coated liposomes calculated with the total and tumorous clearance of the drug was ca. 5 times larger than that of non-coated liposomes. We ascertained that polymers having a hydrophobic moiety in the molecule such as PVA-R and HPMC-R are suitable materials for modifying the surfaces of the doxorubicin-loaded liposome to improve its targeting properties.

We intended to develop a desired ointment base suitable for treatment of bedsores including the proliferation of granulation and epidermis. The main bedsore bacteria detected in our hospital were S. aureus in gram-positive coccus and P. aeruginosa in gram-negative bacillus. As the macrogol ointment (MO) was found to have bactericidal effects on these bacteria, MO was adopted as the base for the objective ointment. To improve the properties of the ointment base such as regulating the humidity of the exudation and controlling the release of antibiotics formulated in the ointment, co-formulating effects of various additives to MO were evaluated. The sustained release function of the ointment base was obtained by adding hydrophilic petrolatum (HP) to MO. However, the resultant ointment was found to have a poor humidity regulating property. On the other hand, MO containing 5% of hydroxypropyl cellulose (HPC) showed both the humidity regulating and the controlled drug releasing properties. It was considered that HPC particles dispersed in the ointment could be swelled by absorbing water to form a gel network. The curd tension meter tests for the ointments prepared with the various polymers showed that the MO-HPC base, which showed the highest sustained drug releasing property, was found to have the highest hardness. This result means that HPC formulated into the base forms the most rigid gel structure to resist the erosion of the ointment and to control the drug release.

Modification to find the best physicochemical properties of minocycline hydrochloride ointment for optimum treatment of bedsore was investigated by coformulating various types of cyclodextrins (CyD) in the ointment base. It was found that the drug release rate from the ointment base was modified according to the preparation method of ointment base and the type of CyD admixed. The physicochemical properties, such as viscosity, elution volume, water absorption of ointment base were also modified by those factors. The mechanism of physicochemical modification with CyD was explained by the structural change of ointment base and the change of surface tension of emulsifying agent solution with the CyD. The stability of ointment was investigated by confirming the reproducibility of drug release rate after storage at ambient and cooled temperature conditions. In conclusion, a fused mixed ointment with beta-CyD was found to be preferable for treatment of bedsore, because of the improved drug release rate, lowered viscosity and increased elution volume of the resultant ointment.

The purpose of this study was to investigate the temperature-induced crystallization and the compactibility of the composite particles containing amorphous lactose and various types of polymers. The composite particles were prepared by spray-drying an aqueous solution of lactose and various types of gel forming water-soluble polymers at various formulating ratios. The stabilizing effect of hydroxypropylcellulose (HPC) and polyvinyl pyrrolidone (PVP) on amorphous lactose in the composite particles was smaller than that of sodium alginate in comparing at the same formulating ratios. The difference in the stability of amorphous lactose in the composite particles was attributed to the difference in the glass transition temperature (Tg) of the composite particles caused by the polymers formulated. The tensile strength of compacted spray-dried composite particles containing the polymers was higher than commercial lactose for direct tabletting (DCL21). The tensile strength of the composite particles was increased with an increase in water content in the particles. The difference in compactibility of the composite particles containing the different amount of polymer and water could be explained by the difference in Tg of the particles.

A desired ointment bases for better treatment of bedsores was developed to improve the release rate of minocycline hydrochloride (MH) and the water absorption capacity using various types of hydrophobic to hydrophilic ointment base. The influence of purified lanolin (PL) on the release behavior of MH from hydrophilic ointment (HO) base was primarily focused on. It was found that the release rate of drug increased with increase in the hydrophilicity of the base. A linear correlation between the apparent release rate constant of drug from the HO and PL mixed ointment base at various combination ratios and the elution of ointment base was noted. The HO ointment base containing 30% PL had the highest apparent release rate constant of MH. The mixed ointment base with the lowest viscosity showed the highest absorption of water and elution of ointment base. In conclusion, it was found that HO (70%) and PL (30%) mixed ointment base was a promising candidate for better treatment of bedsores.

The relative contribution of stearoyl-CoA desaturase and 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase, which are induced by peroxisome proliferators, to the increase in the proportion of oleic acid in C-2 position of phosphatidylcholine (PtdCho) in the liver of rats was investigated. Rats were administered either 4-chlorophenoxyisobutyric acid (clofibric acid), 2,2'-(decamethylenedithio)-di-ethanol (tiadenol) or perfluorooctanoic acid in varying doses. With administration of these peroxisome proliferators, the proportion of oleic acid in C-2 position of PtdCho in hepatic microsomes was increased in commensurate with the increase in activities of stearoyl-CoA desaturase and 1-acyl-GPC acyltransferase. Multiple regression analysis revealed that although there is a high correlation among the three parameters examined, the partial correlation between the proportion of oleic acid in the C-2 position and the activity of stearoyl-CoA desaturase is significantly higher than that between the proportion of oleic acid in the C-2 position and the activity of 1-acyl-GPC acyltransferase. The contribution of stearoyl-CoA desaturase to the increase in the proportion of oleic acid in the C-2 position thus appears greater than that of 1-acyl-GPC acyltransferase.

Metabolic changes induced by p-chlorophenoxyisobutyric acid (clofibric acid) in hepatic phosphatidylethanolamine (PtdEtn) were studied. The treatment of rats with clofibric acid increased the hepatic concentrations of phosphatidylcholine (PtdCho), PtdEtn and phosphatidylinositol (PtdIns), but not phosphatidylserine (PtdSer). Among the phospholipids, the extent of increase of PtdEtn was the most prominent (1.91-fold on the basis of g liver and 2.73-fold on the basis of whole liver). Of the enzymes which are involved in the synthesis de novo of PtdEtn, the activity of cytidine 5'-triphosphate (CTP): phosphoethanolamine cytidylytransferase was reduced by the administration of clofibric acid to rats. The treatment of rats with this drug significantly decreased the serum concentration of free ethanolamine. Clofibric acid enhanced the activity of PtdSer decarboxylase and depressed the N-methylation in vivo of PtdEtn by inhibiting N-methyltransferase. Moreover, clofibric acid significantly depressed the turnover of PtdEtn, which was labeled in vivo with [3H]glycerol. These results suggest that, under the influence of clofibric acid, hepatocytes facilitate the pathway PtdCho-->PtdSer-->PtdEtn and reduce the turnover of PtdEtn, resulting in an expanded cellular pool of PtdEtn.

Structure-Ca2+ antagonistic activity relationships of semotiadil (1) congeners having a benzothiazine cyclic system were studied quantitatively by the Hansch-Fujita method. A quadratic dependency of the activity on ClogP, a lipophilic descriptor, of terminal arylalkylamine moieties was suggested. A correlation between the dipole moment component of the 5'-substituted 2-phenylbenzothiazine parts and the potency was also suggested. Additionally, quantitative analysis was successfully shown for the 2-substituted 1 congeners. The results gave information about the mode of binding of 1 with Ca2+ receptor.

We have recently reported that 4-[2-(4-substituted phenylsulfonylamino) ethylthio]phenoxyacetic acids and related compounds showed potent thromboxane A2 (TXA2) receptor antagonist activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) was analyzed by using the Hansch-Fujita method for 36 compounds, including newly synthesized compounds. The positive coefficient for pi R and FR in the results of the QSAR study suggested that a hydrophobic an sigma electron-withdrawing substituent R at the para-position of the phenylsulfonyl moiety is required to improve the activity. Further, a substituent R which is long and moderately wide, was suggested to be preferable for the activity. The positive coefficients for pi X,Y,W-COOH and sigma Q(1)-(6) may indicate that the introduction of a hydrophobic and electron-withdrawing group on the benzene ring of the phenoxy acetic acid moiety enhances the activity. The length of the W-COOH moiety may also be important. On the other hand, the effect of the presence of methylene (n = 1) was not clear.

A series of 1,2,3,4-tetrahydro-beta-carbolines has been synthesized and evaluated for cerebral protecting effects against lipid peroxidation and potassium cyanide intoxication in mice. Most of the compounds synthesized had potent effects against lipid peroxidation. Among them, 1-(3,5-dimethoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline (22) was found to have a combination of potent effects against both lipid peroxidation and potassium cyanide intoxication. Structure-activity relationships are discussed.

Multilamellar liposomes consisting of dipalmitoyl phosphatidylcholine (DPPC) and dicetyl phosphate (DCP) in a molar ratio of 8:2 (DPPC:DCP = 8:2) were coated with three different types of polymers: chitosan, polyvinyl alcohol having a long alkyl chain, and poly(acrylic acid) bearing cholesterols. The existence of polymer layers on the liposome surface was confirmed by measuring the zeta potential of the liposomal particles. The mucoadhesive function of the polymer-coated liposomes was evaluated in vitro using rat intestine. A particle counting method using the Coulter counter was adopted to evaluate the adhesive % of liposomes. Chitosan coated liposomes showed the highest adhesive % among the polymer-coated liposomes tested. No adhesive % was observed for the non-coated liposomes. The adhesion of chitosan-coated liposomes to the intestine wall was confirmed by fluorescence microscopy using pyrene loaded liposomes.

We prepared chitin-containing cis-diamminedichloroplatinum(II) (CDDP) albumin microspheres with various particle sizes, and investigated in vitro CDDP release; the antitumor effect towards VX2 tumor introduced into rabbits was then examined. It was found that the rate of release of CDDP from chitin-containing CDDP albumin microspheres in vitro was increased with reduced particle size. Administration of microspheres to VX2 tumor-bearing rabbits via the hepatic artery resulted in different profiles of plasma platinum concentration depending on the particle size, and a higher concentration of platinum was released from the beginning of administration as particle size was reduced. The platinum content in hepatic tissue following the administration of CDDP microspheres was increased as the particle size decreased, although the rate of increase was not uniform. The antitumor effect of CDDP assessed by the suppression of tumor growth tended to be higher when microspheres of smaller sizes were used. However, no significant difference was observed in tumor growth rate between rabbits injected with microspheres smaller than 20 microns and those injected with sizes between 20 and 37 microns (p > 0.05). We also examined the relationship between the CDDP dose and antitumor effect using microspheres of less than 20 microns and observed a dose-dependent antitumor effect. No significant difference was observed, however, between 2 and 4 mg eq CDDP/kg dose levels (p > 0.05). From these results, we concluded that microsphere size and CDDP dose were strongly correlated with the augmentation of antitumor effect of chitin-containing CDDP albumin microspheres used in chemo-embolization therapy via the hepatic artery.

In order to develop new-generation macrolide antibiotics active against erythromycin (EM)-resistant strains, a series of 6-O-methyl EM 9-O-substituted oxime derivatives was synthesized and evaluated for antibacterial activity against EM-resistant (S. aureus J-109) and susceptible (S. aureus 209P) strains. To understand how substituents affect the biological activity, the quantitative structure-activity relationships (QSAR) was analyzed using the Hansch-Fujita method. With the EM-resistant strain, the positive coefficient for log P may indicate that higher hydrophobicity of molecules is favorable for antibacterial activity. The negative coefficients of the Sterimol parameters L, B1, and B5 may indicate that long, bulky substituents are unfavorable. With the EM-susceptible strain, the negative coefficient for log P may indicate that hydrophilicity is important for antibacterial activity. A short substituent is also required to improve the activity. Based on the QSAR model, a derivative (87) having an anthracenylmethyl moiety was synthesized to reinforce and confirm the correlation. The activity of 87 against the EM-resistant strain was significant. In QSARs of 6-O-methyl EM-A 9-O-substituted oxime derivatives, the difference of the contribution of log P to the antibacterial activity between EM-resistant and susceptible strains was clearly recognized.

A series of 3-benzoyl or 3-phenylsulfonyl-2-substituted thiazolidine derivatives were synthesized, and evaluated for their thromboxane A2 (TXA2) receptor-antagonizing effect on (15S)-15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5(Z),13(E)-dienoic acid (U-46619)-induced aggregation of rabbit platelet-rich plasma (PRP). A simple 2-aryl-thiazolidine derivative, 3-benzoyl-2-(4-hydroxy-3-methoxyphenyl)thiazolidine (5a), showed mild TXA2 receptor antagonist activity. Modification of 5a led to 2-chloro-4-[3-(4-chlorophenylsulfonyl)thiazolidin-2-ylmet hyl]phenoxyacetic acid (29d), which showed 10 times more potent TXA2 receptor antagonist activity than 5a.

Rats and mice were fed a diet, prepared with soybean oil (SO), perilla oil (PO) or fish oil (FO), for 4 weeks. Compared with the groups of SO-feeding, FO-feeding increased content of eicosapentaenoic acid (20:5 n-3), docosapentaenoic acid (22:5 n-3) and docosahexaenoic acid (22:6 n-3) and PO-feeding elevated the content of alpha-linolenic acid (18:3 n-3), 20:5 n-3 and 22:5 n-3 or hepatic lipids of both rats and mice. FO-feeding increased the activity of peroxisomal beta-oxidation in the livers of both rats and mice. The activities of peroxisomal beta-oxidation in rats and mice that were fed FO diet at a high fat (40% of energy) concentration corresponded to 20% and 30%, respectively, of the maximum activities induced by peroxisome proliferators (4-chlorophenoxyisobutyric acid or perfluorooctanoic acid). To a lesser extent, PO-feeding elevated this activity too. There were significant correlations between peroxisomal beta-oxidation activity and the content of either 20:5 n-3, 22:5 n-3 or 22:6 n-3 in hepatic lipids. FO-feeding decreased effectively serum level of cholesterol of both rats and mice. The reduction in serum cholesterol by feeding PO was less pronounced than that observed with FO-feeding. A high correlation was found between 22:6 n-3 content in hepatic lipids and serum concentration of cholesterol. Although FO-feeding lowered the level of circulating triacylglycerol, PO-feeding produced no change. No substantial correlation was observed between the hepatic content of n-3 fatty acid and the concentration of serum triacylglycerol.(ABSTRACT TRUNCATED AT 250 WORDS)

1,4-Dihydropyridine derivatives having two nitrooxyalkyl moieties as esters at the 3 and 5 positions possess antihypertensive activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) of 27 compounds was analyzed using the Fuzzy adaptive least-squares (FALS 91) method. The QSAR models suggested that the hydrophobicity and electronic effect at the 4 position of the 1,4-dihydropyridine along with the special structures of the nitrooxyalkylester components are important for antihypertensive activity.

In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound 1b (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed.

A series of N-(mercaptoalkyl)thiazolidine-2-thiones and their derivatives were synthesized and evaluated for hepatoprotective activities against Propionibacterium acnes-lipopolysaccharide (P. acnes-LPS)-induced liver injury in mice and in vitro lipid peroxide (LPO) formation in rat liver microsomes. Reaction of N-(p-methoxybenzylthioalkyl)cysteine methyl ester (11) with 1,1'-thiocarbonyldiimidazole followed by deprotection gave the corresponding thiazolidine-2-thione derivatives. Among the compounds synthesized, 1a and 2a showed the most potent hepatoprotective activities against P. acnes-LPS-induced liver injury. Compounds 1a-f and 4 inhibited LPO formation in vitro. Compounds 1a and 2a were chosen for further pharmacological evaluations.

3-Benzoylpropionic acid derivatives possess an immunomodulative activity and suppress adjuvant arthritis. To understand how substituents affect the biological activity, the quantitative structure-activity relationships of 30 compounds were analyzed by the adaptive least-squares method. For the suppressing activity in rats, the electronic effects and the structural feature of the substituent on benzene ring were suggested to be important. To reinforce and confirm the correlation, 4 additional compounds of phenoxybutyric acid derivatives were synthesized and tested with the rat adjuvant-induced arthritis. These compounds were found to have potent suppressing activity.

Prolonged-release spherical micro-matrices of ibuprofen with Eudragit RS were prepared using a novel emulsion-solvent diffusion method. Those particles were termed "microspheres" due to their characteristic sponge-like texture and unique dissolution and compression properties unlike conventional microcapsules or microspheres. The internal porosity of microspheres could be easily controlled by changing the concentration of the drug and the polymer in the emulsion droplet (ethanol). With lower concentration of ibuprofen in the ethanol, the resultant microspheres had a higher porosity, about 50%. The drug release rate from the microspheres was interpreted by the Higuchi model of spherical matrices, which depended only on their internal porosity of the microspheres when size distribution and drug content were the same. The tortuosities in the microspheres were found to be almost constant (3-4) irrespective of porosity, suggesting the same internal texture. Microsphere compressibility was much improved over the physical mixture of the drug and polymer owing to the plastic deformation of their sponge-like structure. The more porous microspheres produced stronger tablets [corrected].

The absorption characteristics of vitamin E acetate (VEA) formulated into a dry emulsion system after its oral administration to beagle dogs were determined and compared to those of two different dosage forms (an oily mixture of the drug with cottonseed oil and an oil (drug)-in-water emulsion). The three dosage forms were administered in a crossover fashion to six nonfasting subjects, and the drug absorption was assessed from the plasma concentration of the major metabolite (free vitamin E). VEA formulated in the dry emulsion was rapidly absorbed, which suggested that a considerable amount was released as reformed emulsion droplets in the gastrointestinal tract as well as in water in vitro. Based on the analysis of variance, no significant differences in bioavailability parameters (AUC, Cmax or Tmax) were observed among the three dosage forms.

A series of 3-acylidene-4-methylazetidin-2-one derivatives bearing various substituents at the 1-position of the azetidin-2-one ring was synthesized. These compounds were evaluated for platelet aggregation inhibitory activities. Most of the compounds synthesized showed potent inhibitory activities against rabbit platelet aggregation induced by adenosine diphosphate or collagen in vitro. Structure-activity relationships are also discussed.