Minimally required heat doses for various tumour sizes in induction heating cancer therapy determined by computer simulation using experimental data.

PURPOSE: Although induction heating cancer therapy (IHCT) using magnetic nanoparticles can be a promising approach to treatment-less multi-nodular cancers, the objective requirement for successful clinical application has not clearly been elucidated. We intended to define objective heat doses suitable for IHCT, especially focusing on the sizes of liver cancer nodules. MATERIALS AND METHODS: Alternating magnetic fields were applied to three human pancreatic cancer cell lines, the intercellular space of those cell pellets were filled with magnetic nanoparticles, and confirmed the cytotoxic effect of IHCT. Subsequently, the temperatures of liver cancer nodules in IHCT were simulated using a computer software program and the required heat dose for various sized tumours were determined. RESULTS: Heating the cancer cells up to 50 degrees C for 10 min was sufficient for complete cell killing and the heat dose of 1.7 W/g(tumour) is required for 10 mm tumour. Larger tumours require a smaller heat dose, e.g. 20 mm and 40 mm tumours require 0.7 W/g(tumour) and 0.6 W/g(tumour), respectively, whereas smaller tumours require large amounts of heat, e.g. 5 mm and 1 mm tumours require 5.1 W/g(tumour) and 105 W/g(tumour), respectively. CONCLUSIONS: Integrating the presently available technologies, including high-quality magnetic nanoparticles (1000 W/g(material)) and effective drug delivery systems (1-2 mg(material)/g(tumour)), treatment of a 10 mm tumour seems possible. Since treatment of smaller tumours less than 5 mm require substantial heat dose, researchers involved in IHCT should target cancer nodules of 10 mm or more, and develop a heat delivery system providing a minimum of 1.7 W/g(tumour).

Potent protecting effects of Catuaba (Anemopaegma mirandum) extracts against hydroperoxide-induced cytotoxicity.

Ishigami et al. (Ishigami et al., 1998) reported that squalene monohydroperoxide (SQOOH) induced skin damage in hairless mice. Kohno and Takahashi (Kohno and Takahashi, 1993) reported that SQOOH induced cytotoxicity against Chinese hamster lung fibroblasts. We have already evaluated the efficacy of extracts obtained from Brazilian herbal medicines in protecting the normal human epidermis keratinocytes [NHEK(B)] against the cytotoxicity caused by SQOOH. The EtOAc extract was separated by silica-gel column chromatography into eight fractions. Fractions (Fr) 1,3 and 5 significantly protected rat basophilic leukemia (RBL-2H3) cells from the release of beta-hexosaminidase due to SQOOH. Additionally, Fr5-1 was most effective in a Gunze three-dimensional cultured human skin model (Vitrolife-skin) against the cytotoxicity due to SQOOH and the release of interleukin (IL)-2 and IL-4. The mixture of cinchonains Ia and Ib and the mixture of cinchonains IIa and IIb were isolated from Fr3 and Fr5-1, respectively. The results suggest that the addition of SQOOH caused the reduction in cell viability and the release of beta-hexosaminidase and cytokines as chemical mediators. The extract of Catuaba (Anemopaegma mirandum) prevented these toxic effects with the main active agents suggested to be cinchonains IIa and IIb.

Two novel cucurbitacins, neocucurbitacins A and B, from the Brazilian folk medicine "Buchinha" (Luffa operculata) and their effect on PEBP2alphaA and OCIF gene expression in a human osteoblast-like Saos-2 cell line.

Two novel cucurbitacins designated as neocucurbitacins A (1), possessing inhibitory activity of polyoma enhancer binding protein 2alphaA (PEBP2alphaA) and osteoclastogenesis-inhibitory factor (OCIF) gene expression in human osteoblast-like cells, and B (2) were isolated from the fruit of Luffa operculata. Their structures have been determined by extensive spectroscopic investigation.

[Origin of sennosides in health teas including Malva leaves].

The aim of this study is to clarify whether sennosides are contained in the leaf of Malva verticillata L., and then to clarify the source of sennosides in health teas including malva leaves. The identification and determination of sennosides were performed with thin layer chromatography and high performance liquid chromatography. The leaf of Malva verticillata L. did not contain sennosides A or B and could be easily distinguished from senna leaf. Our previous report showed that sennosides are contained in weight-reducing herbal teas including malva leaves, and that senna leaf is a herbal component in some teas. Furthermore, in 10 samples of health tea including malva leaves that were bought last year, the smallest amount of sennosides was 6.1 mg/bag, and all health teas including malva leaves contained the leaf and midrib of senna. We suggest that sennosides A and B are not contained in the leaf of Malva verticillata L., and that the sennosides in health teas including malva leaves are not derived from malva leaf but from senna leaf.

New sesquiterpene lactones from Elephantopus mollis and their leishmanicidal activities.

The leishmanicidal compounds isolated from whole plants of Elephantopus mollis H.B.K. were identified as follows. Three new sesquiterpenoid lactones, 2,5-epoxy-2beta-hydroxy-8alpha-(2-methylpropenoyloxy)-4(15),10(14),11(13)-germacratrien-12,6alpha-olide, (4betaH)-8alpha-(2-methylpropenoyloxy)-2-oxo-1(5),10(14), 11(13)-guaiatrien-12,6alpha-olide and (4betaH)-5alpha-hydroxy-8alpha-(2-methylpropenoyloxy)-1(10),11(13)-guaiadiene-12,6alpha-olide, were isolated from Peruvian and Brazilian collections together with four known sesquiterpenoids, molephantin, elephantopin, isoelephantopin and 2-deethoxy-2beta-methoxyphantomolin. They exhibited potent in vitro leishmanicidal activities against Leishmania major. The alpha-methylene-gamma-butyrolactone moiety was found to be essential to the potent leishmanicidal effect observed.

Anti-androgenic triterpenoids from the Brazilian medicinal plant, Cordia multispicata.

Compounds 1-6 were isolated from the AcOEt soluble fraction of leaves of the Brazilian medicinal plant, Cordia multispicata, and their structures were elucidated to be 3beta,25-epoxy-21beta-acetoxy-3alpha,22beta-dihydroxyurs-12-en-28-al (1), 3beta,25-epoxy-28-acetoxy-3alpha,21beta,22beta-trihydroxyurs-12-ene (2), 21beta-acetoxy-22beta-hydroxy-3-oxours-12-en-28-al (3), 28-acetoxy-6beta, 21beta,22beta-trihydroxy-3-oxours-12-ene (4), 21beta,22beta-dihydroxy-3-oxours-1 2-en-28-al (5) and 3beta,21beta,22beta-trihydroxyurs-I2-en-28-al (6), respectively, by means of spectral data, especially two dimensional NMR techniques. Triterpenes having the hemiketal structure at the A-ring, an acyloxy group at C-22 and/or ketone at C-3 showed potent anti-androgenic activity.

A new secoiridoid glucoside, amaronitidin, from the Peruvian folk medicine "Hercampuri" (Gentianella nitida).

A new secoiridoid glucoside designated amaronitidin (1) was isolated from the Peruvian folk medicine "Hercampuri" (Gentianella nitida) along with three known secoiridoid glucosides. Their structures were determined by extensive spectroscopic investigation.

Sesterterpenoid from Gentianella alborosea.

The structure of a new type of sesterterpenoid, designated as alborosin, isolated from Gentianella alborosea, has been deduced from a spectroscopic investigation.

Monoamine oxidase inhibitory naphthoquinone and/or naphthalene dimers from Lemuni Hitam (Diospyros sp.), a Malaysian herbal medicine.

From the extract of a Malaysian herbal medicine, Lemuni Hitam (Diospyros sp.), which exhibited monoamine oxidase (MAO) inhibition, three new naphthoquinone and/or naphthalene dimers (lemuninols A-C, 1-3) were isolated together with 4,6-dihydroxy-5-methoxy-2-methyl-naphthalene (8) and six known monomers (4-7, 9 and 10). The structures were determined by spectroscopic methods including 2D-NMR techniques. Among them, lemuninol A showed 45% inhibition of MAO (mouse liver) at 5.0 x 10(-6) g/ml, and lemuninols B and C and a naphthoquinone (9) indicated weak activity. Some related quinones were also tested for their MAO inhibitory activities.

A novel sesterterpenoid, nitiol, as a potent enhancer of IL-2 gene expression in a human T cell line, from the Peruvian folk medicine "Hercumpuri" (Gentianella nitida).

A novel sesterterpenoid designated as nitiol (1), possessing enhancement activity of IL-2 gene expression in a human T cell line, was isolated from the Peruvian folk medicine "Hercampuri" (Gentianella nitida). The structure was elucidated by extensive spectroscopic investigation.

[Geobotanical studies on the island of Tanegashima (affinity of world property island Yakushima)].

A list was drawn up of wild plants growing on Tanegashiama island that were identified in our field work, and the list was compared with the flora of the rest of Japan and the flora of Taiwan. There were 166 families and 1,218 species consisting of 23 families and 159 species of Pteridophyta, 4 families and 7 species of Gymnosperma, 113 families and 700 species of the dicotyledous Angiosperma, and 26 families and 353 species of monocotyledous Angiosperma. There are 229 families and 5,500 species of plants in Japan, 196 families and 3,019 species in Kyushu, and 228 families and 3,477 species in Taiwan. There are 11 species of endemic plants on Tanegashima and Yakushima, and the best known of them is Pinus armandii Francht. var. amamiana Hatsushima. There are 181 species of flora of flora limited to the northern element, including several important medicinal plants, such as Akebia quinata Decaisne and Zanthoxylum piperitum DC. The 69 species of flora limited to the southern element include several important tropical plants, such as Messerschmidia argentea Johnston and Clerodendrum inerme Gaertn. Most of these plants are distributed on both island, but some of are distributed only Tanegashima. We concluded that one of the temperate borderlines of Japanese flora in the temperate zone is the islands of Tokara. The flora of Tanegashima and Yakushima are having a closely affinity of plant species and having the rich plant species.

Colony stimulating factor-inducing activity of isoflavone C-glucosides from the bark of Dalbergia monetaria.

To obtain immunomodulating substances from Amazonian medicinal plants, hot water extracts from 21 samples available commercially were tested in terms of mitogenic and colony-stimulating factor (CSF)-inducing activities. Among them, Dalbergia monetaria exhibited the highest CSF-inducing activity. Orobol 8-C-glucoside (OCG-8) and orobol 6-C-glucoside (OCG-6) were isolated from the bark of D. monetaria as major constituents. The CSF-inducing activity of OCG-8 was higher than that of OCG-6 and a dose-dependent manner at a range of 0.1-10 mg/mouse. Serum CSF production induced by an intraperitoneal (i.p.) injection with 1 mg OCG-8 reached a peak at 4-6 h later, suggesting that OCG-8 would act on hematopoietic system.

Enhancement of serum nitric oxide by Shichimotsu-koka-to (Kampo medicine).

The Kampo medicine Shichimotsu-koka-to (SKT) is used to treat hypertension and atherosclerosis in Japan. The action of SKT was studied, focusing on nitric oxide, which is intimately involved in regulation of blood pressure and cell functions associated with atherogenesis and inflammation. Oral administration of SKT enhanced serum nitric oxide (NOx) levels dose-dependently and 3 d administration was enough to detect its effect. The maximal level of serum NOx was maintained at around 27 microM, a concentration which did not result in harmful effects on cells. On the other hand, L-arginine, the substrate of NO synthase (NOS), was also increased by SKT administration. When the source of L-arginine was studied, only 12.7 mg of L-arginine was contained in 1 g of SKT and this amount of L-arginine could not explain the increased L-arginine levels in serum. These results suggest that SKT may enhance serum L-arginine by acting on L-arginine metabolism, but not by supplying L-arginine itself, resulting in enhancement of serum NOx. In conclusion, the antihypertensive and antiatherosclerotic action shown by SKT may be in part due to enhanced serum NOx, thus suggesting that SKT may become a unique orally active drug for cardiovascular diseases as a new NO donor.

Preventive effects of Shichimotsu-koka-to on renal lesions in stroke-prone spontaneously hypertensive rats.

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.

[The utilization and safety of medicinal plants and crude drugs].

Recently, herbal remedy and health caring food are widely used throughout the generation. These main plant materials have been characterized and classified into 5 categories, by the Ministry of Health and Welfare (MHW), Japanese Government, in 1971, which include 3 medicine divisions and 2 food divisions. These categories, having only limited number of plants, were quite difficult to classify the newly imported plant materials. In order to solve this problem, each category was updated to include new herbal materials in March 1998. Kampo medicines are Japanese traditional medicines, which has been used for the patients mostly by doctors of western medicine and 3 kinds of Kampo prescription had been reevaluated by the drug reevaluation system of Japan. But, along with the expanding consumption of the Kampo medicines in the clinical treatments, several side effects of the Kampo medicines has recently been reported by the collection of adverse reaction data of MHW, these side effects are important signals for believing the safety of natural drugs. The chapter I is definition of medicinal plant and crude drugs, and chapter II is reported of WHO guidelines for the traditional medicines. Chapter III is 4 section; 1. safety of the medicinal plants and crude drugs is included the poisonous plant and the side effect of Kampo medicines, 2. the pesticide for the crude drugs in Japanese Pharmacopoeia, 3. limited test of contamination of microorganisms, 4. Identification of medicinal plant names. Chapter IV is the definition of drugs and food. The chapter V is the drugs type materials used in young generation for hallucinogenic or sexual purpose. Chapter VI is the stance to research work for the new drugs from plant gene resources in the world.

[Aristolochic acids in herbal medicines].

Aristolochic acids are nitrophenanthrenes with a carboxylic acid fanction which have been found only among the Aristolochiaceae. In 1993, rapidly progressive interstitial renal fibrosis has been reported in women have been on a slimming regimen including Chinese herbal medicines in Belgium. In Japan, at the Kansai district, several cases of Chinese herbs nephropathy have been reported quite recently. In both cases, aristolochic acids was detected in the Chinese herbal medicines taken by the patients. We have Asiasarum Root, a species of Aristolochiaceae, in Japanese Pharmacopoeia. Therefore, we quantitatively analysed aristolochic acids in these herbal medicines and related plants.

[Calcium oxalate crystals in several kinds of Cinnamon bark].

OBJECTIVE: To probe into the morphology and distribution characteristics of calcium oxalate crystals in several kinds of Cinnamon bark. METHOD: Forty samples of ten different species of Cinamomi Cortex were examined, and the inter-cellular calcium oxalate crystals in the phloem rays were observed by optical microscope and scanning electron microscope. RESULT: It was found that for samples of the same botanical origin, there is little variation in the crystal morphology following certain regularity. The amount, size and ultra-micromorphologic characteristics are influenced by various factors. CONCLUSION: The pattern of morphology and distribution of calcium oxalate crystals may well be an index for identification of the crude drug of Cinnamon bark.

Antiandrogenic natural Diels--Alder-type adducts from Brosimum rubescens.

The isolation and structure elucidation of five novel natural Diels--Alder-type adducts, named palodesangrens A-E (1-5), from the Peruvian folk medicine known as "palo de sangre" (Brosimum rubescens) is described. The structures of the Diels--Alder adducts, consisting of chalcone derivatives and a prenylcoumarin, were elucidated by analysis of spectroscopic data including 2D NMR. Some of these compounds showed potent inhibitory activity towards 5 alpha-dihydrotestosterone (DHT) binding with an androgen receptor to form a DHT-receptor complex that causes androgen-dependent diseases.

Antiinflammatory effect of Forsythia suspensa Vahl and its active fraction.

This study was carried out to elucidate the antiinflammatory effect of 70% methanol extract obtained from the dried fruit of Forsythia suspensa Vahl and its active principles. F. suspensa was extracted with 70% methanol and freeze-dried to give a powdered extract. The methanol extract was then dissolved in water and extracted with n-hexane, and the n-hexane fraction was evaporated to dryness under vacuum; the water fraction was freeze-dried to give a powdered extract. The antiinflammatory activity of the extract and fractions was investigated on acetic acid-induced vascular permeability and writhing symptoms in mice, as well as on carrageenin-induced edema and cotton pellet-induced granuloma formation in rats. The methanol extract and the n-hexane fraction (p.o.) showed the antiinflammatory effect and analgesic effect, but the water fraction did not. These results suggested that the antiinflammatory and analgesic activity induced by the methanol extract shifted to the n-hexane fraction and the active principles may be lipophilic compounds.

Antiandrogenic phenolic constituents from Dalbergia cochinchinensis.

Four new compounds, 9-hydroxy-6,7-dimethoxydalbergiquinol, 6-hydroxy-2,7-dimethoxyneoflavene, 6,4'-dihydroxy-7-methoxyflavan and 2,2',5-trihydroxy-4-methoxybenzophenone, in addition to eight known phenolic compounds including 7-hydroxy-6-methoxyflavone, have been isolated from the stems of Dalbergia cochinchinensis. Their structures were established by spectroscopic techniques including one- and two-dimensional NMR methods. The first two compounds showed potent inhibitory activity towards 5 alpha-dihydrotestosterone (DHT) which binds with an androgen receptor to form a DHT-receptor complex that causes androgen-dependent disease.