Terpenoids biotransformation in mammals III: Biotransformation of alpha-pinene, beta-pinene, pinane, 3-carene, carane, myrcene, and p-cymene in rabbits.

The biotransformation of (+)-, (-)-, and (+-)-alpha-pinenes, (-)-beta-pinene (nopinene), (-)-cis-pinane, (+)-3-carene, (-)-cis-carane, myrcene, and p-cymene in rabbits was investigated. The major metabolites were as follows: (-)-trans-verbenol from (+)-, (-)-, and (+/-)-alpha-pinenes; (-)-10-pinanol and (-)-1-p-menthene-7,8-diol from (-)-beta-pinene; (-)-alpha-terpineol and (-)-trans-sobrerol from (-)-cis-pinane; (-)-m-mentha-4,6-dien-8-ol, 3-caren-9-ol, (-)-3-carene-9-carboxylic acid, and 3-carene-9,10-dicarboxylic acid from (+)-3-carene; carane-9,10-dicarboxylic acid from (-)-cis-carane; and myrcene-3(10)-glycol, myrcene-1,2-glycol, uroterpenol, and p-cymene-9-carboxylic acid from p-cymene. These metabolisms include allylic oxidation, epoxidation, stereoselective gem-dimethyl hydroxylation and its oxidation, cleavage of a conjugated double bond by epoxidation, and regioselective oxidation, some of which are not found usually in chemical reactions, and due to which various new compounds were determined. This biotransformation of the monoterpene hydrocarbons gave some insect pheromones in high yield.U

Terpenoid biotransformation in mammals. II: Biotransformation of dl-camphene in rabbits.

The biotransformation of dl-camphene in rabbits was investigated. Four neutral metabolites, 6-exo-hydroxycamphene, 10-hydroxycamphene, and diastereoisomers of camphene-2,10-glycol, were identified and two alcohols, 7-hydroxycamphene and 3-hydroxytricyclene, were estimated by IR, UV, NMR, and mass spectra and chemical degradations. The formation of these compounds can be explained through a homoallylic oxidation or an epoxide formation.

Usefulness of tc-99m MIBI SPECT in predicting multidrug resistance gene expression levels in non-small cell lung cancer--a preliminary report.

In this study we investigated whether Tc-99m hexakis 2-methoxy isobutyl isonitnile (Tc-99m MIBI) single-photon emission computed tomography (SPECT) has a correlation with the multidrug resistance (MDRI) and multidrug resistance-associated protein (MRP1) gene expression levels in non-small cell lung cancer (NSCLC). Fifteen patients with NSCLC were studied. SPECT images were obtained 15 (early) and 120 (delayed) min after injection of Tc-99m MIBI. We chose only one transverse section and set the region of interest over the tumor and out of the body. The mean counts in the tumor on early and delayed images were corrected by using those in the background and represented as Te and Td, respectively. Resected tumor specimens were frozen with liquid nitrogen and each positive control cell line was cultured. After the total ribonucleic acid (RNA) was extracted from specimens and cell lines, the complimentary deoxyribonucleic acid (cDNA) was amplified by the reverse transcription-polymerase chain reaction (RT-PCR) method. Each product was electrophoresed and fluorointensity was measured. The gene expression level was represented as the ratio of that of the positive control cell line. Te and Td indicated a significant correlation with the MDR1 gene expression level (p = 0.015 and p = 0.022), but not the gene of MRP1 (p = 0.100 and p = 0.145). In conclusion, Te and Td are useful parameters in predicting the MDRI gene expression level, but not MRPI in NSCLC.

Serial changes in N-isopropyl-p[125I]-iodoamphetamine in mouse lung observed with a confocal laser scanning microscope.

Serial changes in N-isopropyl-p[125I]-iodoamphetamine (125I-IMP) in mouse lungs were observed with a confocal laser scanning microscope. Male mice were intravenously injected with 125I-IMP and subjected to autoradiographic procedures 20 minutes, and 3 and 24 hours after injection. Differential interference contrast (DIC) images and confocal images were obtained with a confocal laser scanning microscope, and superimposed images were evaluated. Large numbers of silver grains were observed in the interstitium, bronchioles, and alveolar sacs 20 minutes after the injection, and lamellar distribution of the grains was observed on the ciliary surface. The numbers of silver grains in the interstitium and bronchioles had decreased 3 hours after the injection of 125I-IMP, but the numbers of silver grains in the alveolar spaces had not. Although small numbers of silver grains remained in both the bronchioles and alveolar sacs 24 hours after the injection, most of them had washed out. Confocal laser scanning microscopy is considered to be a useful procedure for studying the distribution of radioisotopes by microautoradiography, because it allows clear autoradiographs to be obtained in which tissues and silver grains are perfectly matched and all silver grains are in focus.

Technetium-99m MIBI single photon emission computed tomography as an indicator of prognosis for patients with lung cancer-preliminaly report.

PURPOSE: We performed technetium-99m hexakis-2-methoxyisobutylisonitrile (Tc-99m MIBI) single photon emission computed tomography (SPECT) in 23 patients with primary lung cancer between July 1993 and March 1996. We evaluated the relationships among the uptake ratio, retention index and the prognosis after radiation therapy and/or chemotherapy. MATERIALS AND METHODS: Tc-99m MIBI SPECT was performed at 30 minutes and at 3 hours after intravenous injection of 600 MBq of Tc-99m MIBI with three gamma camera detectors (GCA-9300A/HG) on transverse SPECT images. Regions of interest were set in the area of abnormal uptake of Tc-99m MIBI and in the contralateral normal lung. The ratio of uptake in the lesion to that in the contralateral normal lung was obtained on early images (early ratio; ER) as well as delayed images (delayed ratio: DR). The retention index (RI) was calculated as follows: RI = (DR - ER)/ER x 100. The ratio was compared with survival time and prognostic factors. RESULTS: There was no correlation between ER and DR. The patients with high RI survived longer than those with low RI (median survival, 19.4 months vs. 9.4 months; p = 0.0104 by the Mantel-Cox test). CONCLUSION: These results suggest that RI is the most useful among Tc-99m MIBI indices of primary lung cancer in predicting prognosis.

Utility of Tc-99m GSA whole-body scintigraphy in detecting bone metastases from hepatocellular carcinoma.

Recent advances in the treatment of hepatocellular carcinoma (HCC) have prolonged patient survival. However, the number of patients with bone metastases identified during follow-up examinations has increased. Tc-99m Sn-N-pyridoxy-5-methyltryptophan (Tc-99m PMT) has been reported to accumulate at a high rate in HCC lesions and bone metastases. In the patient described here, whole-body scintigraphy showed accumulation of DTPA galactosyl human serum albumin (Tc-99m GSA) and Tc-99m PMT in bone metastases from HCC. The authors suggest that asialoglycoprotein receptors may be present in bone metastases from well-differentiated HCC. Tc-99m GSA whole-body imaging can be used to detect bone metastases from HCC and to evaluate hepatic reserve.

Pharmacological studies of 2-(3-(3-(1-piperidinylmethyl)-phenoxy)propylamino)-4 (3H)-quinazolinone (NO-794), a new histamine H2-receptor antagonist.

The pharmacological profile of a new histamine H2-receptor antagonist, 2-(3-(3-(1-piperidinylmethyl)phenoxy)propylamino)-4 (3H)-quinazolinone (NO-794), was studied. NO-794 was a potent and selective histamine H2-receptor antagonist in the guinea-pig atria and gastric mucosal cells. NO-794 (1 X 10(-5) M) did not interact with H1-, muscarinic and beta 1-receptors. In guinea-pig atria, antagonism of NO-794 was unsurmountable. The onset of action of NO-794 was slow, and this antagonism was apparently irreversible not only on the guinea-pig atria but also on the gastric mucosal cells. In addition, NO-794 inhibited gastric acid secretion in pylorus ligated rats when administered intraduodenally. These results indicate that NO-794 is a powerful and unique histamine H2-receptor antagonist and may be useful in the treatment of peptic ulcer.

Antitumor agents, 90. Bruceantinoside C, a new cytotoxic quassinoid glycoside from Brucea antidysenterica.

Three cytotoxic, quassinoid glycosides, the new bruceantinoside C [1] and the known yadanziosides G [2] and N [3] were isolated from the stem of Brucea antidysenterica. The structures of 1-3 were determined from their spectral data.

[Evaluation of tiquizium bromide (HSR-902) as an antiulcer agent].

The effects of HSR-902, an antimuscarinic agent, on development of various gastric and duodenal lesions, gastric secretion, pupil size and salivation in rats were compared with those of pirenzepine.2HC1 (pirenzepine, antiulcer agent) and timepidium bromide (timepidium, antispasmodic). 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently inhibited the developments of gastric lesions induced by water-immersion stress, aspirin, indomethacin, serotonin and reserpine and duodenal lesions induced by cysteamine and mepirizole. The activities of HSR-902 were almost equal or somewhat more potent than those of pirenzepine, and they were more potent than those of timepidium. 2) HSR-902 (30 and 100 mg/kg, p.o.), when examined using pylorus-ligated preparations, dose-dependently inhibited the gastric acid output, pepsin output, and gastric acid and pepsin concentrations, but did not inhibit the gastric volume (HSR-902, in a higher dose, slightly increased the gastric volume.). Pirenzepine (100 mg/kg, p.o.), like atropine sulfate, inhibited the gastric volume, acid output and pepsin output, but did not inhibit the gastric acid and pepsin concentrations. Timepidium (100 mg/kg, p.o.), however, hardly influenced these parameters except for increasing the gastric volume. 3) HSR-902 (100 mg/kg, p.o.) induced the mydoriasis and inhibited the pilocarpine-induced salivation, and its activities were less potent than those of pirenzepine. These results suggest that HSR-902 is a promising agent for the treatment of peptic ulcer.

[Cytoprotective activity of tiquizium bromide (HSR-902) and its mechanism].

The effects of HSR-902, an antimuscarinic agent, on acute gastric mucosal lesions induced by various necrotizing agents, gastric mucus secretion and gastric HCO3- secretion in rats were compared with those of pirenzepine.2HCl (pirenzepine), an antiulcer agent. 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently prevented the gastric mucosal lesions induced by ethanol-HCl (60% ethanol in 150 mM HCl), aspirin-HCl (150 mg/kg of aspirin in 150 mM HCl), 0.6 N HCl and 0.2 N NaOH; and the cytoprotective effects of HSR-902 were almost equal or somewhat more potent than those of pirenzepine. 2) HSR-902 (30 mg/kg, p.o.), like pirenzepine, increased the alcian blue binding to gastric mucosa and both hexosamine and N-acetylneuramic acid in gastric juice and reversed the decrease of alcian blue binding to gastric mucosa in water-immersion stress. 3) HSR-902 (30 mg/kg, p.o.), unlike pirenzepine and atropine sulfate, increased the gastric HCO3- secretion in the pylorus-ligated preparations. 4) The cytoprotective effect of HSR-902 (30 mg/kg, p.o.), when examined using gastric mucosal lesion induced by aspirin-HCl, was not abolished by the pretreatment with indomethacin (10 mg/kg, s.c.) or N-ethylmaleimide (10 mg/kg, s.c.). 5) HSR-902 (30 mg/kg, p.o.) did not influence the gastric mucosal potential difference. These results suggest that HSR-902 is a promising drug for the treatment of gastritis and peptic ulcers.

Antitumor agents, 79. Cytotoxic antileukemic alkaloids from Brucea antidysenterica.

Two cytotoxic antileukemic alkaloids, the new 1,11-dimethoxycanthin-6-one (3) and the known 11-hydroxycanthin-6-one (1), as well as the known canthin-6-one (2) were isolated from the stem of Brucea antidysenterica. The structures of 1-3 were determined from their spectral data and X-ray analysis of the o-bromobenzoate of 1.

Bone mass and lifestyle related factors: a comparative study between Japanese and Inner Mongolian young premenopausal women.

The purpose of this study was to evaluate the ethnic difference in bone mass between Japanese and Inner Mongolian young premenopausal women and to assess the contribution of lifestyle related and anthropometric factors to bone mass. We studied 33 Japanese and 44 Inner Mongolian healthy young women, aged 20-34 years, in urban area. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) were measured at the calcaneus using quantitative ultrasound (QUS) analysis. Age at menarche, regularity of menstruation and lifestyle related factors were estimated by a self-reported questionnaire. There were no differences between the two groups in age, height, weight, BMI, regularity of menstruation, frequency of meat intake, frequency of yellow-green vegetable intake and exercise habit. Japanese women had significantly lower age at menarche and higher proportion of milk consumption habit at junior high school, senior school and present. Before adjustment, Japanese women had significantly higher SOS and SI than Inner Mongolian women. However, after adjustment for age at menarche and milk consumption habit at junior high school, both of which were significantly different between groups, no group-differences remained in either SOS or SI. These results suggest that the differences in age at menarche and milk consumption habit at junior high school, which relate to hormonal and nutritional status during puberty, may account for the differences in bone mass between Japanese and Inner Mongolian young women.