SHAPE ESTIMATION OF BOWTIE FILTERS BASED ON THE LUMINESCENCE FROM POLYETHYLENE TEREPHTHALATE RESIN BY X-RAY IRRADIATION.

In this study, we devised a novel method estimating the bowtie filter shapes by imaging luminescence from a polyethylene terephthalate (PET) resin with X-ray irradiation in a computed tomography (CT) scanner. The luminescence distribution of the PET resin corresponding to the thickness of bowtie filter was imaged using a charge-coupled device camera. On the assumption that the material of bowtie filter is aluminium (Al), the shape of bowtie filters was estimated from the correlation between Al attenuation curves and the angular-dependent luminance attenuation profiles according to the thickness of bowtie filters. Dose simulations based on the estimated bowtie filter shapes were performed using head and body PMMA phantoms with 16 and 32 cm in diameter. The simulated values of head and body weighted CT dose index (CTDIw) based on bowtie filter shape by the luminescence imaging method agreed within ~9% with the measured values by a dosemeter.

MEASUREMENT OF INTERNAL RADIATION DOSE DISTRIBUTION IN CT EXAMINATIONS USING POLYETHYLENE TEREPHTHALATE RESIN.

This study proposes a new dosimetry method for the estimation of the internal radiation dose distribution of a subject undergoing computed tomography (CT) examinations. In this novel method, dose distribution of a subject by CT scans was estimated based on radiophotoluminance distribution with polyethylene terephthalate (PET) resin which was cut to the average head size of a Japanese 1-year-old child. The difference in dose distribution depending on the type of bowtie filter was visualized by imaging luminance distribution with the PET phantom using a charge-coupled device camera. Dose distribution images simulated from a water phantom of the same size as the PET phantom were compared with the luminance distribution images. The linear correlation was demonstrated between luminance of the PET phantom and the simulated water dose. In comparison with the simulated water doses and the converted water doses from luminance of the PET phantom, the relative differences were within 20%.

New phenylpropanoid esters of sucrose from Polygonum lapathifolium.

Four new phenylpropanoid esters of sucrose, lapathosides A (1), B (2), C (3), and D (4), were isolated from the aerial parts of Polygonum lapathifolium together with known esters, vanicoside B (5) and hydropiperoside (6). The structures of 1-4 were determined by spectral (1D and 2D NMR and MS) analysis. Lapathoside A (1) and vanicoside B (2) showed significant inhibitory effects on the Epstein-Barr virus early antigen activation by tumor-promoters.

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents.

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Cancer chemopreventive activity of carotenoids in the fruits of red paprika Capsicum annuum L.

Capsanthin and related carotenoids isolated from the fruits of red paprika Capsicum annuum L. showed potent in vitro anti-tumor-promoting activity with inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among them, capsanthin diester and capsorbin diester showed strong inhibitory effects. Furthermore, capsanthin , capsanthin 3'-ester and capsanthin 3,3'-diester , major carotenoids in paprika, exhibited potent anti-tumor-promoting activity in an in vivo mouse skin two-stage carcinogenesis assay using 7, 12-dimethylbenz[a]anthracene as an initiator and TPA as a promoter.

Antitumor-promoting effects of cyclic diarylheptanoids on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

Eleven cyclic diarylheptanoids were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. 13-Oxomyricanol and myricanone showed the highest activity and also exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that certain diarylheptanoids might be valuable antitumor promoters and/or chemopreventors.

Flavonoid and benzophenone glycosides from Coleogyne ramosissima.

A benzophenone glucoside and two flavonol glycosides were isolated together with 27 known polyphenols from the aerial parts of Coleogyne ramosissima, and their structures were elucidated by spectroscopic and chemical methods as iriflophenone 2-O-beta-glucopyranoside, isorhamnetin 3-O-2G-rhamnopyranosylrutinoside-7-O-alpha-rhamnopyranoside and limocitrin 3-O-rutinoside-7-O-beta-glucopyranoside, respectively.

Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies.

A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.

Anti-tumor promoting activity of polyphenols from Cowania mexicana and Coleogyne ramosissima.

Chemical investigation on polyphenol-rich fractions of Cowania mexicana and Coleogyne ramosissima (Rosaceae) which showed significant inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), has led to the characterization of 10 compounds including C-glucosidic ellagitannin monomers and dimers from the former plant, and 17 polyphenols including flavonoid glycosides from the latter. The effects of individual components and their analogues with related structures on the TPA-induced EBV-EA activation were then evaluated. Among the compounds isolated from C. mexicana, two C-glucosidic ellagitannins, alienanin B and stenophyllanin A and a nitrile glucoside (lithospermoside), and among the constituents from C. ramosissima, two flavonoid glycosides, isorhamnetin 3-0-beta-D-glucoside and narcissin were revealed to possess strong inhibitory effects on EVB-EA activation, the potencies of which were either comparable to or stronger than that of a green tea polyphenol, (-)-epigallocatechin gallate. These polyphenols except for nitrile glucoside, which was not tested owing to an insufficient amount, were also found to exhibit anti-tumor promoting activity in two-stage mouse skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) and TPA.

An antitumor promoter from Moringa oleifera Lam.

In the course of studies on the isolation of bioactive compounds from Philippine plants, the seeds of Moringa oleifera Lam. were examined and from the ethanol extract were isolated the new O-ethyl-4-(alpha-L-rhamnosyloxy)benzyl carbamate (1) together with seven known compounds, 4(alpha-L-rhamnosyloxy)-benzyl isothiocyanate (2), niazimicin (3), niazirin (4), beta-sitosterol (5), glycerol-1-(9-octadecanoate) (6), 3-O-(6'-O-oleoyl-beta-D-glucopyranosyl)-beta-sitosterol (7), and beta-sitosterol-3-O-beta-D-glucopyranoside (8). Four of the isolates (2, 3, 7, and 8), which were obtained in relatively good yields, were tested for their potential antitumor promoting activity using an in vitro assay which tested their inhibitory effects on Epstein-Barr virus-early antigen (EBV-EA) activation in Raji cells induced by the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). All the tested compounds showed inhibitory activity against EBV-EA activation, with compounds 2, 3 and 8 having shown very significant activities. Based on the in vitro results, niazimicin (3) was further subjected to in vivo test and found to have potent antitumor promoting activity in the two-stage carcinogenesis in mouse skin using 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and TPA as tumor promoter. From these results, niazimicin (3) is proposed to be a potent chemo-preventive agent in chemical carcinogenesis.

Antitumor agents. 190. Absolute stereochemistry of the cytotoxic germacranolides, tomenphantins A and B, from Elephantopus tomentosus.

The structures and absolute stereochemistries of tomenphantins A (1) and B (2), cytotoxic germacranolides isolated from Elephantopus tomentosus, are reported herein. 1H and 13C NMR spectroscopic data, chemical transformation, and single-crystal X-ray analysis were used in these determinations.

Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids.

Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 microg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 microg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 microg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 microg/mL), it was slightly toxic (IC50 6.5 microg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1beta-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0. 0005 microg/mL and a T. I. value of 22 400.

Effect of nonsteroidal anti-inflammatory drugs on lipid peroxidation by hydroxyl radical.

1. Effects of acetaminophen and sodium salicylate on hydoxyl radical elimination were studied using an electron-spin-resonance spin-trapping method. The effects of these agents on lipid peroxidation of the human erythrocyte membrane were also investigated by the thiobarbituric acid method. 2. Acetaminophen and sodium salicylate depressed hydroxyl radical generated by Cu2+/H2O2. 3. Acetaminophen inhibited Cu2+/H2O2-dependent lipid peroxidation; however, sodium salicylate enhanced Cu2+/H2O2-dependent lipid peroxidation.

Anti-tumor promoting activities of isoflavonoids from Wistaria brachybotrys.

Eight minor isoflavonoids (3-10) isolated from the knot of Wistaria brachybotrys were tested for their inhibitory effects on Epstein-Barr virus (EBV) activation induced by the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), in Raji cells as a primary screening test for anti-tumor-promoters (cancer chemopreventive agents), and all the tested compounds showed inhibitory activity. Of these compounds, pendulone (3) was further examined on the cell cycle of Raji cells, and indicated strong inhibition on the effect of the cell cycle induced by TPA. In addition, the compound showed potent anti-tumor-promoting activity for an in vivo two-stage carcinogenesis test of mouse skin using 7,12-dimethylbenz[a]-anthracene and TPA. Consequently, it suggests that 3 could be a valuable chemopreventive agent in chemical carcinogenesis.

Inner ear disorders due to pressure change.

We reviewed the records of 136 patients who had inner ear disorders including hearing loss and vertigo caused by pressure change. We divided them into three groups, according to the aetiology: group A, change in atmospheric pressure (diving, airplane travel, etc.); group B, rapid change in ear pressure in normal atmosphere (nose blowing, heavy lifting, etc.); and group C, blast injury. A flat initial audiogram was the most common type in groups A and B. In group C, high-tone hearing loss was the most common type of audiogram. These results correspond to findings previously reported in animal experiments. Exploratory tympanotomy was performed more than 12 days after the pressure change in 16 patients. Although the vertigo disappeared after surgery, hearing did not improve.

[Electrophysiological study of inner ear barotrauma in guinea pigs; comparison with scanning electron microscopic findings].

To investigate the mechanism of barotrauma to the inner ear, we used electrophysiologic methods to evaluate guinea pigs exposed to such trauma, and compared the findings with those observed by scanning electron microscopy (SEM). Guinea pigs with good Preyer's reflexes were studied. In those animals that showed a loss of or decrease in Preyer's reflexes and/or nystagmus following exposure to an increase and decrease in pressures in a high-pressure chamber, we measured compound action potentials (CAPs) and cochlear microphonics (CMs) 7-11 days after the exposure. The pressure was increased from 1 ATA to 2 ATA over 30 sec and maintained for 10 min, then pressure was decreased to 1 ATA over 30 sec. Specimens obtained from animals in which CAPs and CMs could be measured were prepared for SEM examination. CAPs and CMs were measured at decreasing 5 dB increments to the visual threshold level of detection with tone bursts at 1, 2, 4 and 8 kHz. Based on the CAPs measured 7-11 days after exposure, guinea pigs were divided into two groups by CAP thresholds, those with severe damage and those with mild damage. None of the animals showed moderate damage. The group with high CAP thresholds showed severe damage to hair cells on SEM, while the group with low CAP thresholds showed no specific morphological abnormalities on SEM. It appeared that some guinea pigs with normal SEM findings following barotrauma to the inner ear did not achieve complete recovery of hearing. From these results, it was speculated that some animals had sustained reversible damage in the mild group and that these animals had recovered from moderate damage. The elevation of CMs was usually not high compared to that of CAPs in the high frequency area, and 4 animals showed CAP and CM separation above 30 dB at 8 kHz. These findings suggested that the group with severe damage exhibited multiple patterns of injury.

Morphological studies on middle ear barotrauma in guinea pigs.

Experimental middle ear barotrauma was studied morphologically. White guinea pigs were placed in an experimental hyperbaric chamber, and middle ear barotrauma was created by increasing the pressure in the hyperbaric chamber from 1 atmosphere absolute (ATA) to 2 ATA using pure oxygen, maintaining the pressure at 2 ATA for 10 minutes, then again reducing the pressure to 1 ATA. Selected experimental animals were decapitated immediately after, one day after, one week after, or weeks after pressure loading, and their middle ears were examined by a light microscope (LM), a scanning electron microscope (SEM) and a transmission electron microscope (TEM). Hemorrhaging in the tympanic cavity immediately after pressure exposure was apparent even macroscopically. LM also revealed evidence of submucous hemorrhage. Submucous edema was seen in the "one week after" cases. SEM showed a minor loss of cilia in some ciliated cells just after the experiment. In nonciliated cells, the terminal web was somewhat indistinct in the "one week after" cases. TEM also indicated a minor loss of cilia in some ciliated cells in "one day after" cases as well as apparent vacuoles within the cells. These findings suggest that although trauma during compression is more marked than during decompression, recovery from this damage progressed with time.

[Scanning electron microscopic study of inner ear barotrauma: in the guinea pig under hypobaric pressure].

In order to investigate the mechanism of inner ear barotrauma, guinea pigs, with bilateral eustachian tube occlusion, were subjected to decompression and compression between 760 and 460 mmHg in a hypobaric pressure chamber. We divided the guinea pigs into two groups, A and B. Group A showed normal eustachian tubes, and group B showed bilaterally occluded eustachian tubes. Group B animals were divided into three types according to the rates of compression and decompression. After pressure loading, morphological changes in the hair cells of the organ of Corti were studied by means of scanning electron microscopy. There was no damage to hair cells in the setting of normal eustachian tube function, as in group A. On the other hand, mild to severe hair cell damage was observed with rapid decompression in group B. This observation suggests that relative positive pressure in the middle ear cavity is an important factor in inner ear barotrauma. The mechanism of hair cell damage due to inner ear barotrauma is presumed to be distortion of the organ of Corti caused by a difference in pressure between perilymph and endolymph resulting in injury to the stereocilica.

Changes in levels of monoamines and their metabolites in incompletely ischemic brains of spontaneously hypertensive rats.

In order to investigate changes in levels of monoamines and their related substances together with those of other neurotransmitters (acetylcholine and GABA), choline and substances related to energy metabolism (ATP, lactate and glucose) accompanying incomplete cerebral ischemia, a bilateral common carotid artery occlusion model of spontaneously hypertensive rats (SHR) was utilized. Animals were subjected to 1 or 2 h ischemia. Then the concentrations of substances were measured in the cerebral cortex, hippocampus and striatum and compared with control values. Due to the incomplete ischemia, ATP showed a moderate decrease, while lactate and choline increased remarkably, and GABA underwent a moderate increase. With regard to monoamines, both noradrenaline and serotonin levels were reduced in the cerebral cortex and hippocampus, whereas dopamine levels increased in the hippocampus. All monoamine metabolites, i.e. metabolites by monoamine oxidase (MAO), metabolites by catechol-O-methyltransferase (COMT), and metabolites by both MAO and COMT, underwent increases. The 3-methoxytyramine level in particular showed marked increases. Furthermore levels of precursor amino acids as well as 5-hydroxytryptophan rose. Acetylcholine decreased moderately only in the cerebral cortex. Among these changes, sustained increases in all the monoamine metabolites were characteristic of changes in the incompletely ischemic brain, suggesting that both COMT and MAO retain their activities in the incompletely ischemic brain.

Antitumor agents, 154. Cytotoxic and antimitotic flavonols from Polanisia dodecandra.

Three flavonols, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone [1], 5,4'-dihydroxy-3,6,7,8,3'-pentamethoxyflavone [2], and quercetin 3-O-beta-D-glucopyranosyl-7-O-alpha-L-rhamnopyranoside [3], were isolated from Polanisia dodecandra. Compound 1 showed remarkable cytotoxicity in vitro against panels of central nervous system cancer (SF-268, SF-539, SNB-75, U-251), non-small cell lung cancer (HOP-62, NCI-H266, NCI-H460, NCI-H522), small cell lung cancer (DMS-114), ovarian cancer (OVCAR-3, SK-OV-3), colon cancer (HCT-116), renal cancer (UO-31), a melanoma cell line (SK-MEL-5), and two leukemia cell lines (HL-60 [TB], SR), with GI50 values in the low micromolar to nanomolar concentration range. This substance also inhibited rubulin polymerization (IC50 = 0.83 +/- 0.2 microM) and the binding of radiolabeled colchicine to tubulin with 59% inhibition when present in equimolar concentrations with colchicine. Compound 2 also showed cytotoxicity against medulloblastoma (TE-671) tumor cells with an ED50 value of 0.98 microgram/ml. Compound 1 appears to be the first example of a flavonol to exhibit potent inhibition of tubulin polymerization and, therefore, warrants further investigation as an antimitotic agent.