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The effect of the histamine H2 receptor antagonist, ranitidine, on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism, in five volunteers. Acetaminophen (1000 mg) together with ranitidine (300 mg), placebo or at 1 h after ranitidine (300 mg) was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. Plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were determined by HPLC. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves from each volunteer. The area under the plasma acetaminophen concentration-time curve from 0 to 3 h (AUC0–3) significantly (P < 0.01) increased from 13.03 ± 0.84 μg h mL−1 (placebo coadministration) to 21.30 ± 0.60 μg h mL−1 (ranitidine coadministration). The peak plasma acetaminophen concentration significantly (P < 0.01) increased from 18.30 ± 2.26 μg mL−1 (placebo coadministration) to 34.14 ± 1.07 μg mL−1 (ranitidine coadministration) 30 min after administration. Plasma acetaminophen concentrations with ranitidine were significantly increased at 15 to 120 min compared with placebo. Plasma acetaminophen glucuronide conjugate concentrations with ranitidine were significantly decreased at 15 to 45 min compared with placebo, whereas plasma acetaminophen sulphate conjugate concentrations were not significantly altered. Plasma acetaminophen and acetaminophen conjugate concentrations were not significantly different between placebo-coadministration and in the case where acetaminophen was orally administered 1 h after ranitidine. Coadministration of acetaminophen and ranitidine reduced plasma acetaminophen glucuronide concentrations and significantly increased plasma acetaminophen concentrations. The effects of ranitidine are as a result of the prevention of first-pass hepatic metabolism, by prevention of acetaminophen glucuronyltransferase. Thus care must be taken when acetaminophen and ranitidine are coadministered.

Photocleavage of the NO bond of N -(9-anthroyloxy)-9-fluorenylideneamine takes place efficiently in acetonitrile in the excited singlet state attributed to the fluorenylidene moiety. This made it possible for the first time to directly observe 9-anthroyloxyl radicals. However, the efficiency decreases remarkably in benzene in which the lowest excited singlet state is attributed to the anthroate moiety.

A significant directive effect of the 2-axial hydroxy group appeared in the LiAlH4, NaBH4, and Zn(BH4)2 reduction of cyclohexanone, while the 3-axial hydroxy group exhibited a steric hindrance. The distance between the carbonyl carbon and the hydroxy group which interacts with the hydride reagent is mainly responsible for such a difference. In the reduction of Na[B(OAc)3H], both the 2- and 3-axial hydroxycyclohexanones exclusively gave the products which were obtained by the hydride approaching from the side of the hydroxy group. The key point of this stereoselectivity is the formation of Na[B(OAc)2(OR)H], which is far more reactive than the parent hydride, by exchanging the acetate ion with the alkoxide.

The complex metal hydride reductions of 2-t-butyl-1,3-dioxan-5-one (1) and 3-oxoquinolizidine (3) are faster than those of the corresponding carbocyclic compounds, 4-t-butylcyclohexanone (2) and trans-2-decalone (4). The stereoselectivities were similar in the LiAlH4 reduction, but the heteracyclohexanones exhibited higher stereoselectivity with NaBH4. These facts are discussed in terms of the intramolecular orbital interaction.

Quenching of imidazoyl radical (Im•) formed in photoinitiator systems comprising an aminostyryl-dye and a radical generating reagent by a 2-rnercaptobenzothiazole (MBT):aminostyryl-dye; 2-[p- (diethylamino)styryl]naphtho[1, 2-d]thiazole (NAS), radical generating reagent; 2, 2′-bis(2-chlorophenyl)- 4, 4′, 5, 5′-tetraphenyl-1, 1′-bi-1H-imidazole (BI) in a poly(methyl methacrylate) film has been investigated by laser flash photolysis using a total reflection cell.

A sensitive and specific double-antibody enzyme immunoassay (EIA) for adrenocorticotropic hormone-like immunoreactive substances (ACTH-ISs) was developed. In competitive reactions, the ACTH (1-24)-antibody was incubated with both ACTH (1-24) standard (or sample) and 13-D-galactosidase labeled synthetic human ACTH (1-24) (delayed addition). The free and antibodybound enzyme haptens were separated by using an anti-rabbit IgG coated immunoplate. The activity of the enzyme on the plate was fluorometrically determined. The present immunoassay allows for the detection of 2 to 600 fmol/mL of ACTH (1-24). Using the proposed EIA, ACTH (1-24)-ISs in human plasma were thus determined. As a result, the levels of ACTH (1-24)-ISs in human plasma were found to be about 3.7 fmol/mL.

The electrochemical properties of a series of cis-dioxobis(dithiocarbamato)molybdenum(VI) complexes [MoO2(RR′dte)2] (RR′dte = N,N-disubstituted dithiocarbamate) and the oxygen atom transfer reactions between [MoO2(RR′dte)2] and PPh3 in 1,2-C2H4Cl2 at 25°C are systematically investigated. A good correlation between logarithmic values of second-order rate constants k1 of the oxygen atom transfer reactions and redox potentials E°′ for [MoO2OP2RR′dte)2]01couples is observed over the wide range of k1 (from 0.012 to 0.61 M s+2); the values of log k1 linearly increase with the increase of E0. The departure from the correlation line is exactly observed for [MoO2(Bz2dte)2/PPh2 [MoO2(Ph2dte)2]/PPh1 and [MoO2(BzPhdte)2]PPh1 systems. A negative activation entropy (ΔS′ = −114 J mol+1K+1) of the oxygen atom transfer reaction obtained for the [MoO2(Et2dte)2]/PPh4 system indicates that the reaction proceed through an associative process. These results suggest that an attack of a lone pair of PPh4 on an oxo ligand and a negative charge flow to the molybdenum center occurs to form an activated complex. The anomaly observed for [MoO2(Bz2dte)2]/PPh4, [MoO2(Ph2dte)2]/Pph4 and [MoO2(RR′dte)2]. Other physicochemical properties of the complexes such as 11C NMR and Mo O stretching frequencies in solutions and the X-ray crystal structure of cis-dioxibis(thiomorpholydithiocarbamato)molybdenum(VI) are also reported.

In order to get insight into the effect of the different fixations of the conjugated systems of the aminochalcone-dyes on both the photophysical behavior and the quenching scheme of photoinitiation systems in a film, photophysical behavior of 2-benzoyl-6-(dimethylamino)benzo[b]furan (A) on 355 nm excitation with or without a radical-generating reagent, 2,4,6-tris(trichloromethyl)-1,3,5-triazine (TRI), in poly(methyl methacrylate) (PMMA) film has been investigated by laser flash photolysis using a total reflection cell. Dye A showed characteristic dual fluorescences of which the lifetimes, τSs, of shorter- and longer-wavelength components were evaluated to be 3.2 and 5.4 ns, respectively. The fluorescences were quenched by TRI with different static quenching distances, (Rs)Ss, of 1.3 and 1.5 nm for Ashort and Along, respectively. The static quenching distance of the initial triplet absorption of A, (Rs)T, was evaluated to be 1.5 nm. In addition, deconvolution analysis of the lifetimes of fluorescent dyes h...

The crystal structures of two binuclear iron(III) complexes with linear μ-oxo bridge, Fe2OCl2 (tfpy)2 (ClO4)2 ·2CH3CN and Fe2OCl2(epy)2(ClO4)2 were determined, where (tfpy) and (epy) represent N,N-bis(2-pyridylmethyl)-tetrahydrofurfurylamine and N,N-bis(2-pyridylmethyl)-2-ethoxyethylamine, respectively. Their structural features are essentially the same as that of the corresponding linear binuclear complex with (tpa)-complex, Fe2OCl2(tpa)2(ClO4)2, where (tpa) is tris(2-pyridylmethyl)amine; the ligands (tfpy) and (epy) act as a tetradentate tripod-like ligand, and Fe-O (ethereal oxygen atom; these are located at the trans-position of bridging oxo-oxygen atom) distances are 2.209(4) and 2.264(2) Å for (tfpy) and (epy) compounds, respectively. These two (tfpy) and (epy) complexes exhibited much higher activity for the oxygenation of cyclohexane in the presence of hydrogen peroxide than that of the (tpa) complex. In contrast to this, the former two complexes exhibit negligible activity for the decomposition of hydrogen peroxide, whereas the catalase-like function of the (tpa) compound is remarkable. These are indicating that an active species for oxygenation of cyclohexane, which is assumed to be an iron(III)-hydroperoxide adduct with η1-coordina­tion mode, should be different from that is operating for decomposition of hydrogen perox­ide; for the latter case formation of a (μ-η1:η1-peroxo)diiron(III) species being stressed. The EHMO calculation showed that electronic interaction between the monodentate hydroperox­ide adduct of the binuclear iron(IIl)-(tfpy) compound and the tetrahydrofuran ring of the ligand system may lead to facile peroxide-tetrahydrofuran linkage formation, and the interac­tion described above should promote the O-O cleavage of the peroxide ion heterolytically. Based on these discussions, it was concluded that heterolytic O-O bond cleavage of the iron(III)-hydroperoxide adduct caused by electronic interaction with organic moiety contain­ing an ethereal-oxygen and by approach of the substrate which donates electron to the perox­ide adduct should play an important role in producing a high-valent iron-oxo species in these systems. In the case of (tpa) complex, formation of a hydroperoxide adduct linking with the ligand system seems to be unfavorable because of both the steric and electronic reasons.

The intramolecular alkoxymercuration of (E)-5-arylpent-4-en-1-ols indicated that the regioselectivity is closely related to the Hammett constants of the para-substituents on the benzene ring. Large solvent effects on the regioselectivity were also observed. These results were compared with those of the methoxymercuration of β-methylstyrene analogues. The regioselectivity is discussed in terms of steric effects as well as the electronic effects which are suggested by the MO calculation for the mercurinium ion intermediates.

Cetraxate hydrochloride (cetraxate), ecabet sodium (ecabet), and sulpiride, which are cytoprotective drugs, have been used to treat peptic ulcers and acute or chronic gastritis. They are reported to improve mucosal blood flow in the stomach. One of the most important factors believed to cause gastric ulcers is mental and/or physiological stress. When people feel stress, the hypothalamo-pituitary-adrenal (HPA) axis is activated. Therefore, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol can be indicators of stress. We examined the effects of cetraxate, ecabet and sulpiride on the plasma levels of ACTH and cortisol under stress conditions by repetitive blood sampling. Venous blood samples were taken before and 20-240 min after a single administration of the drugs or a placebo. A single dose of ecabet caused significant suppression of increases in plasma ACTH-like immunoreactive substance (IS) levels at 90 to 120 min and cortisol levels at 240 min, compared with the response to placebo. Sulpiride only suppressed increases in plasma cortisol levels at 180 to 240 min, compared with the response to placebo. A single dose of cetraxate had no effect on plasma ACTH-IS and cortisol levels. Ecabet may have a modulatory effect on the HPA axis while sulpiride may have a partial modulatory effect on the HPA axis. These effects might be beneficial in stress-related disease.

Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240 min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline.

Impaired renal function has been suggested to significantly impact plasma midregional proADM (MR-proADM) level. The aim of this study was to assess whether improvement of renal function after living kidney transplantation has an impact on plasma MR-proADM-like immunoreactive substance (IS) level. Eleven patients with end-stage renal disease (ESRD) who were scheduled to undergo the first living kidney allograft transplantation were enrolled. Plasma MR-proADM-IS levels were measured before and 3, 7, 10, 14, 21, 30, 60 and 90 days after kidney transplantation. Plasma MR-proADM-IS level decreased significantly from day 3 after kidney transplantation compared to before kidney transplantation. A significant negative correlation was observed between creatinine clearance and plasma MR-proADM-IS level from before to 90 days after kidney transplantation (rs=-0.70, p

The 2- and 3-axially substituted methoxy groups in cyclohexanones exhibit steric hindrance similar to that of the methyl group in LiAlH4 and NaBH4 reductions. The chelate complex formation between the zinc ion and the two oxygens in the molecule was suggested in the zinc borohydride reduction. The relative reactivities of cyclohexanones in which the 2-axial position is substituted by the methyl or the methoxy group in the LiAlH4 reduction strongly support Cieplak’s proposal, which focuses on the importance of the stabilization of the transition state by anti-periplanar allylic bonds.

Two types of self-frequency-doubled Nd:MgO:LiNbO3 laser are demonstrated. Their oscillation polarization directions were controlled for second harmonic generation with new cavity configurations which are smaller than the conventional cavity configuration containing a Brewster window. The first laser uses an etalon effect to select the oscillation polarization direction. It emits 0.27 mW of green light (0.546 μm) from a single side of the cavity in quasi CW mode when the crystal absorbs 33 mW of pump light (0.813 μm) from a laser diode. The second laser has a monolithic cavity and the polarization selection is achieved with angle-walk-off caused by birefringence. It emits about 0.2 mW of green light in quasi CW mode when about 100 mW of pump light is incident. In addition to these experiments, the effectiveness of these polarization selection methods is numerically confirmed.

Preferential hydride attack has been found to occur at the en face, which is the opposite side to the γ-nitrogen atom, of the carbonyl group in the LiAlH4 reduction of 1-azaadamantan-4-one, whose nN orbital is in an equatorial position. On the other hand, hydride attack occurred predominantly from the axial side of 1,2-dimethylpiperidin-4-one and 2-ketoquinolizidine whose nN orbitals are in the axial position. The appreciable solvent effect apparent in the NaBH4 reduction of 1-azaadamantan-4-one may be responsible for the hydrogen bond formation of the nN orbital with the protic solvent. The stereochemistry of the complex metal hydride reduction of γ-azacyclohexanones could be explained by the difference in the non-bonding two electron stabilisation between the incipient σ‡* bond and the antiperiplanar allylic σi bonds which were perturbed by the through-space and/or through-bond interaction with the remote heteroatom.

Sensory afferent neurons in the gastrointestinal mucosa regulate neuropeptides [calcitonin gene-related peptide (CGRP), substance P, etc.], which play various physiologic roles and are gastroprotective. To determine whether the pharmacologic effects of Dai-kenchu-to (DKCT) on the gastrointestine are due to changes in gastrointestinal mucosa regulatory peptide levels, we examined the effects of the DKCT on the levels of CGRP-like immunoreactive substances (IS) and substance P-IS in plasma taken from five healthy subjects. A single oral administration of DKCT 7.5 g caused significant increases in plasma CGRP-IS at 40 min, and in substance P-IS levels at 20 and 60 min, compared with a placebo group. The present study may indicate that the pharmacologic action of DKCT is closely related to changes in CGRP- and substance P-IS levels.

9-Phenanthrenecarboxylic esters as well as naphthalenecarboxylic esters linked with p-methoxystyrene derivatives exert an intramolecular competitive or exclusive oxetane formation through carbonyl addition, although the carbonyl addition is not observed in the corresponding intermolecular systems. The reaction proceeds from the excited singlet state involving plural intramolecular exciplexes. The new aspect of carbonyl addition, i.e., the enhancement of reactivity of the ester carbonyl group by interchromophoric links, is discussed on the basis of photochemical and photophysical observations as well as MO calculations.

Third‐order nonlinear optical properties of As2S3‐based glass fibers are studied at a wavelength of around 1.55 μm. Through time‐resolved pump‐probe measurements and analysis of spectrum broadening due to self phase modulation, it is confirmed that As2S3‐based glass fibers are capable of instantaneous nonlinear refractive response to a subpicosecond pulse. Stimulated Raman scattering (SRS) with a Stokes shift Δk=344 cm−1 is observed using a picosecond pump pulse. The Raman gain coefficient was estimated to be 4.4×10−12 (m/W), which is two orders of magnitude higher than that for silica fiber. The relaxation time of the Raman contribution to nonlinear refraction is estimated to be 97 fs and the influence of the SRS on subpicosecond pulse propagation is observed as a low‐frequency Raman gain. The two‐photon absorption (TPA) coefficient is estimated to be α2=6.2×10−15 (m/W) through a transmission change measurement. The TPA figure of merit for As2S3 glass at a wavelength of 1.55 μm is estimated to be low enough for all‐optical switching applications.

Background: Hormone receptors and proliferation markers are critical parameters for treatment selection of breast cancer patients. The expression of different parameters are currently assessed separately in different tissue sections but it is unclear how different parameters are co-expressed in a single cell in breast cancer tissues. Samples and Methods: Breast cancer tissues from fifty-one patients with ER-positive HER2-negative breast cancer were analyzed. Expressions of ER and PgR were assessed in association with Ki67 using dual fluorescence immunohistochemistry with specific antibodies: SP-1 (abcam, Tokyo), 1E2 (Roche Diagnostics GmBH, Germany), and MIB1 (Dako Japan, Tokyo), respectively. More than 500 cancer cells were assessed in each tissue. Expression levels of each marker in a single cell were semi-quantitatively assessed by MetaMorph image analyzer (Molecular Devices Japan, Tokyo). All statistical analyses were performed using JMP ver.8.01 (SAS Institute Japan, Tokyo). Results: To validate the system, Ki67 LI in breast cancer tissues were compared between this system and the regular DAB system. The two systems showed a good concordance (p < 0.0001). All cancer tissues expressed ER. There were two distinct populations among Ki67-positive proliferating cells according to PgR expression status: PgR-positive proliferating cells and PgR-negative proliferating cells. Since cell proliferation is regulated in cancer cells by at least two different drivers including hormone receptor and growth factor, it is conceivable that these two populations depend on different driving systems. Indeed, tissues with dominantly PgR-positive proliferating cells showed mostly histological grade 1 (15/20, 75%), while most of tissues with PgR-negative proliferating cells showed grade 2 and 3 (22/31, 71%) (p = 0.0025 by chi square test). Moreover, the multivariate analysis using the ordered logistic regression analysis showed that PgR status in proliferating cells is an independent factor associated with histological grade (p = 0.003) while PgR expression rate and Ki67 LI were not (p = 0.3 and 0.25, respectively). Conclusion: PgR status in Ki67-positive proliferating cells is associated with histological grade in ER positive HER2-negative breast cancers. Our results suggest that different driving systems give different expression patterns of PgR and Ki67 at a single cell level, which may distinguish between luminal A and luminal B cancers. Citation Format: Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto. Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3484.

On pulsed laser photolysis of bis(2-bromobenzoyl) peroxide (2-BrBPO) a unique absorption band was observed around 400 nm as well as a broad band due to 2-BrC 6 H 4 CO 2 · radicals in the 500–800 nm region. The 400 nm band was also attributed to 2-BrC 6 H 4 CO 2 · on the basis of the similarity of both absorption in time profiles and behavior towards quenchers. Time-resolved EPR measurements provided clear evidence for some interaction between the CO 2 · radical center and the ortho-bromine atom in 2-BrC 6 H 4 CO 2 · and for the formation of ortho-substituted phenyl radicals, 2-XC 6 H 4 by way of CBr bond cleavage in excited state 2-BrBPO.

Adrenomedullin (ADM) is a 52-amino acid peptide with a variety of physiologic functions such as immunomodulating activity, direct bactericidal activity, maintenance of renal homeostasis, and vasodilatory activity. Midregional proADM (MR-proADM) is derived from a larger 185-amino acid precursor peptide, prepro-adrenomedulin (preproADM), by posttranslational processing. It is suggested to be co-synthesized with ADM in equimolar amounts and has the advantages over ADM in having a longer half-life, no bioactivity, and no binding to protein. Therefore, MR-proADM serves as a surrogate for ADM secretion. In this study, we attempted to develop an enzyme immunoassay (EIA) for quantifying MR-proADM-like immunoreactive substance (IS), which is applicable for monitoring plasma MR-proADM levels. By using β-d-galactosidase-labeled preproADM(83-94) as a marker antigen, anti-rabbit IgG-coated immunoplate as a bound/free separator, and 4-methylumbelliferyl-β-d-galactopyranoside as a fluorogenic substrate, a sensitive and specific EIA was developed for the quantification of MR-proADM-IS in human plasma. The lower limit of quantification was 0.032 pmol/well, and the steep competitive inhibition EIA calibration curve obtained was linear between 0.16 and 10 nmol/L. By using human plasma samples containing 0.2 and 2.0 nmol/L of MR-proADM, the interassay coefficients of variation (reproducibility) were 10.78% and 8.83%, respectively, and intraassay coefficients were 3.91% and 7.81%. Plasma MR-proADM-IS level was significantly higher in patients with chronic renal failure (1.39 ± 0.50 nmol/L) compared with healthy subjects (0.19 ± 0.07 nmol/L). These results suggest that our EIA may be useful to evaluate plasma MR-proADM levels as a biomarker in various clinical settings.

Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains unclear. We examined the correlation of plasma ammonia level with VPA dose and serum trough concentrations of total and free VPA in Japanese patients with epilepsy. Thirty-eight data sets from 19 Japanese patients with epilepsy were analyzed. The relations of VPA dose and serum total and free VPA concentrations with plasma ammonia level, and the breakpoints of VPA parameters predicting hyperammonemia (plasma ammonia higher than 60 µmol/L) were analyzed. A significant positive correlation was observed between plasma ammonia level and VPA dose (r(s)=0.56, p=0.00062), serum trough total VPA concentration (r(s)=0.55, p=0.00086) and serum trough free VPA concentration (r(s)=0.58, p=0.00041). The breakpoints predicting hyperammonemia were VPA dose of 30.4 mg/kg, serum trough total VPA concentration of 90.9 µg/mL, and serum trough free VPA concentration of 8.65 µg/mL, with impurity reductions at 1.35, 1.35 and 2.02, respectively. These findings suggest that serum trough concentration of free VPA is the most reliable predictor for hyperammonemia, and that the risk of developing hyperammonemia may increase in patients with serum trough free VPA concentrations higher than 8.65 µg/mL.

We analyzed the pharmacokinetic-pharmacodynamic relationship of vancomycin to determine the drug exposure parameters that correlate with the efficacy and nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus pneumonia and evaluated the need to use peak concentration in therapeutic drug monitoring (TDM).Serum drug concentrations of 31 hospitalized patients treated with vancomycin for methicillin-resistant S. aureus pneumonia were collected.Significant differences in trough concentration (Cmin)/minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC0-24)/MIC were observed between the response and non-response groups. Significant differences in Cmin and AUC0-24 were observed between the nephrotoxicity and non-nephrotoxicity groups. Receiver operating characteristic curves revealed high predictive values of Cmin/MIC and AUC0-24/MIC for efficacy and of Cmin and AUC0-24 for safety of vancomycin.These results suggest little need to use peak concentration in vancomycin TDM because Cmin/MIC and Cmin are sufficient to predict the efficacy and safety of vancomycin.

Cytochrome P-450 catalyses the oxidative deformylation of trimethyl-acetaldehyde, but not of valeraldehyde. MNDO/PM3 calculations for these C5-aldehydes revealed that the origin of high reactivity of the former aldehyde is due to the electrophilic nature of the intermediate peroxide adduct of P-450, and the comprehensive mechanism of aldehyde metabolism by P-450 is proposed based on the results by EHMO calculations for the peroxide adduct of the iron compound.

In contrast to 2-methylbenzoyloxyl radicals, 2,6-dimethylbenzoyloxyl and 2,4,6-trimethylbenzoyloxyl radicals decarboxylate efficiently rather than transfer a hydrogen atom, as observed by transient absorption spectroscopy and product distribution.

The reactivity of the peroxide adducts of manganese(III) Schiff base complexes towards several organic compounds was investigated by means of electrochemical methods and the results were interpreted in terms of molecular orbital calculations for both metal peroxide adduct and the organic compound. Based on these results, the importance of the electrophilic nature of the peroxide adduct and the electron distribution in the frontier orbital of organic acid anhydride moiety was stressed in order to explain the high reactivity between the two compounds.

Phenanthrene- and naphthalenecarboxylic esters linked with styrene derivatives exert an intramolecular competitive or exclusive oxetane formation depending upon the linking chain length and site, although the carbonyl addition is not observed in the corresponding intermolecular systems. The reaction is a singlet process involving plural exciplexes. The photochemical and, photophysical observations as well as MO calculations indicate that the new aspect of carbonyl addition arises from an apparent enhancement of reactivity of the ester carbonyl group by interchromophoric link; the link destabilizes the exciplexes with conformations achieved in the intermolecular systems and therefore, the exciplexes preferable for carbonyl addition take an important role.

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation and is normally found in human plasma. Because AcSDKP is hydrolyzed by the N-terminal active site of angiotensin converting enzyme and partially eliminated in urine, its plasma level is a result of a complex balance between its production, hydrolysis by ACE, and renal elimination. In this study, we attempted to establish an enzyme immunoassay (EIA) for quantifying AcSDKP-like immunoreactive substance (IS), which is applicable for monitoring plasma AcSDKP levels in healthy subjects and patients with chronic renal failure. Using β-D-galactosidase-labeled Gly-γAbu-SDKP as a marker antigen, an anti-rabbit IgG-coated immunoplate as a bound/free separator and 4-methylumbelliferyl-β-D-galactopyranoside as a fluorogenic substrate, a highly sensitive and specific EIA was developed for the quantification of AcSDKP-IS in human plasma. The lower limit of quantification was 0.32 fmol/well, and the sharp inhibition competitive EIA calibration curve obtained was linear between 8.0 and 513 fmol/ml. This EIA was so sensitive that only 10 µl plasma sample was required for a single assay. The coefficients of variation (reproducibility) for human plasma concentrations of 0.2 and 2.1 pmol/ml were 7.2 and 7.7%, respectively, for inter-assay and 13.3 and 7.8% for intra-assay comparisons. Plasma AcSDKP-IS level was significantly higher in patients with chronic renal failure (0.92 ± 0.39 pmol/ml) compared with healthy subjects (0.29 ± 0.07 pmol/ml). These results suggest that our EIA may be useful to evaluate plasma AcSDKP level as a biomarker in various patients.

Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels.

Isomeric 6,6-diphenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one and 7,7-diphenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (2) were photolyzed in methanol to give rise to unsaturated aldehydes as well as diphenyltetrahydronaphthalene, a decarbonylation product (for 2). Lifetimes of the intermediate triplet biradicals were dependent on their structures, indicating that cyclic conformations play an important role in the intersystem crossing of biradicals.

Intramolecular quenching of the excited singlet state of a phenanthrene moiety was more efficient in (E)-2-(p-methoxyphenyl)-2-butenyl 9-phenanthrenecarboxylate (E-ABP) than in its Z isomer (Z-ABP) in benzene. The quenching is proposed to proceed in a through-space fashion on the basis of efficiencies of isomerization and photophysical processes as well as molecular orbital calculations.

The photorefractive effect in annealed proton-exchanged waveguides in periodically poled nondoped, MgO- and ZnO-doped LiNbO3 was evaluated by monitoring the quasiphase matching (QPM) wavelength shift induced by a 0.784-μm-irradiating light. The QPM wavelength shift was reduced at room temperature by a factor of 3–6 in ZnO- and MgO-doped samples compared with the nondoped samples within a 104–105-W/cm2-irradiation intensity range. The doped samples exhibited no significant wavelength shifts when the temperature was raised to slightly above room temperature (50–60 °C).

We examined the effects of Ninjin-to, a traditional Chinese (Kampo) medicine, on the levels of brain-gut peptides (motilin, vasoactive intestinal peptide (VIP), gastrin, and somatostatin) in plasma from healthy subjects. A single oral administration of Ninjin-to, at a dose of 6.0 g, caused significant increases in plasma motilin levels at 40 to 90 min and somatostatin levels at 20 to 90 min, compared with a placebo treated group. Transient elevations of gastrin levels in the placebo group were inhibited by administration of Ninjin-to, but the medicine did not alter the levels of VIP. In conclusion, these results suggest that pharmacological effects of Ninjin-to on gastrointestinal functions closely relate to changes of motilin, gastrin, and somatostatin-immunoreactive substance levels in human plasma.

Dimethylpiperidinones and dimethylmethylenepiperidines have been hydrogenated over several Group 8, 9 and 10 transition metal catalysts and the stereochemistry of the products compared with those of the carbocyclic analogues. The results obtained suggest that intramolecular interactions between the nitrogen lone pair and the unsaturated bond play a major role in determining the stereochemistry of hydrogenation.

The relative reactivities of cyclohexanones in which the 2-axial position is substituted by methyl or methoxy group in LiAlH4 reduction strongly support the Cieplak model which focuses on the importance of stabilisation of the transition state by antiperiplanar allylic bonds.

Phenanthrene- and naphthalenecarboxylic esters linked with styrene derivatives exert an intramolecular competitive or exclusive oxetane formation depending upon the linking chain length and site, although the carbonyl addition is not observed in the corresponding intermolecular systems. The reaction is a singlet process involving plural exciplexes. The photochemical and, photophysical observations as well as MO calculations indicate that the new aspect of carbonyl addition arises from an apparent enhancement of reactivity of the ester carbonyl group by interchromophoric link; the link destabilizes the exciplexes with conformations achieved in the intermolecular systems and therefore, the exciplexes preferable for carbonyl addition take an important role.

cis -1-amino-1,2,3,4-tetrahydro-2-naphthalenol was synthesized and resolved via its diastereomeric salts. Asymmetric reduction of prochiral ketones was examined using this amino alcohol at various temperatures.

A significant directive effect of the 2-axial hydroxy group appeared in the LiAlH4, NaBH4, and Zn(BH4)2 reduction of cyclohexanone, while the 3-axial hydroxy group exhibited a steric hindrance. The distance between the carbonyl carbon and the hydroxy group which interacts with the hydride reagent is mainly responsible for such a difference. In the reduction of Na[B(OAc)3H], both the 2- and 3-axial hydroxycyclohexanones exclusively gave the products which were obtained by the hydride approaching from the side of the hydroxy group. The key point of this stereoselectivity is the formation of Na[B(OAc)2(OR)H], which is far more reactive than the parent hydride, by exchanging the acetate ion with the alkoxide.

2,4,6-Triphenylpyrylium tetrafluoroborate(TPP + )-sensitized oxygenation has been carried out for several arylalkanes in dichloromethane. Direct evidence for deprotonation of a cation radical was obtained, and interesting structural effects on the deprotonation efficiency was observed.