To Pharmacological Studies
By Prof. Hiroyuki Ageta, President, Organizing Committee
　It is my great pleasure that the International Symposium on Natural Medicines, Kyoto, 1997, will be held in Japan. In 1947 the Japanese Society of Pharmacognosy was established in Kyoto, following the suggestion of Professors Takashi Asahina, Tatsuo Kariyone and others. Thus this Symposium is being held to mark the 50th anniversary of the Society. The membership of the Society increased from fifty to two thousand during these years, and the research focus of pharmacognosy in Japan shifted from botanical studies of natural medicines and chemical studies of natural products to pharmacological studies to develop new drugs. I hope the Symposium will be meaningful for all the delegates. I would like to take this opportunity to thank the many sponsors who have supported this Symposium.

Forum for Global Networking
Prof. Gisho Honda, General Secretary, Organizing Committee
　Although traditional medicines had had to give way to western medicine, they are on the resurgence with the increasing recognition of their efficacy in the treatment of diseases which do not respond well to modern medicine. Currently researches being undertaken include those of plans not traditionally used as natural medicine as well as marine products with focus on medicines kind to the body yet efficacious in treating cancer, degenerative and adult diseases. It is therefore most meaningful that the first International Symposium on Natural Medicines is being held as a forum for the global networking of researchers. It gives me great pleasure to welcome you to Kyoto, where the Japanese Society of Pharmacognosy was established 50 years ago. I hope that the next international symposium will also be held in Asia, the treasure-trove of natural medicines.

Design of Novel Immunosuppressant Based on Fungal Mutabilities
By Prof. Tetsuro Fujita, Chairman, Organizing Committee
　Immunosuppressants are clinically important for organ transplants and autoimmune disease treatment, with success rate increasingly remarkably since cyclosporin. A (CsA) and FK-506 were introduced. However, as high dosages, include dysfunction and other side effects, less toxic drugs are needed to prevent graft rejection. Immunosuppressants ISP-I (myricin=thermozymocidin) and mycestericins A-G were isolated in Isaria sinclairii and Mycelia sterilia cultures, respectively. The mycestericins structures were established based on spectral and chemical evidence and the activity followed by the mouse allogeneic mixed lymphocyte reaction (MLR). Total synthesis of mycestericins D-G was accomplished. To investigate structure, activity relationships and extensive modification of ISP-I was conducted. The reduced compound showed actively fundamental structure possessing the immunosuppressive activity was established to be a symmertrical 2-alky1-2-aminopropane-1, 3-dio1. Of the active modified compounds, ISP-1-55 showed lowest toxicity and was further modified to FTY720 by incorporating a phenyl ring into the side chain. FTY720 shows promise as a safer immunosuppressant. Further hydrophilic modification was examined and the 2-aminoalcohol proved to be the minimum essential structure for immunosuppressive activity. The (R)-is omers were more potent than the (S)-isomers while (R)-2-aminohexadecanol displayed activity comparable to FTY720. ISP-I, ISP-I-55 and FTY720 were found to suppress proliferation of IL-2-dependent CTLL-2, but not production of IL-2 unlike CsA and FK-506, and that ISP-I inhabits serine palmitoyltransferase but ISP-I-55 and FTY720 do not. Structural simplification of ISP-I to 2- substituted 2-aminopropane-1, 3-dio1 and 2-aminoalcohol resulted in biological activity retention but may have altered the biochemical sequence point where the compounds intervene to exhibit immunosuppressive activity. In a rat skin allograft system, oral FTY720 showed synergistic effect in combination with a subtherapeutic dose of CsA.

Search for an Endogenous Mammalian Cardiotonic Factor
By Prof. Koji Nakanishi, Columbia University
　Specific binding of plantderived digitalis glycosides by the mammalian Na, K-ATPase (sodium pump) raised possibility of a mammalian analog of digitalis. The Haupert (Harvard)/ Tymiak (Bristol-Meyers Squibb group), collected 3 ug of HIF hypothalamic inhibitory factor) in 10 years from bovine hypothalamus. Although molecular formula identity and HPLC retention time with ouabain was the same, bioactivity differences were noted (1992). Hence, 300 ng of HIF was naphthoylated for exciton coupled circular dichroic (CD) studies. The HPLC retention time of ouabain pentanaphthorate and the HIF naphthoate, although close, were clearly different; also, although ouabain pentanaphthoate CD showed strong positive exciton couplet of amplitude +379, that of HIF naphthoate was close to nil. On the other hand, the Hamlyn (Maryland)/Ludens (Upjohn) group working with 31 ug of OLC ("oua bain-like compound") from human plasma (300 liters) concluded that OLC was ouaba in. HIF, OLC and ouabain were thus compared by converting 300-400 ng each into their "pentanaphthoates" when it was found that the HPLC retention times of HIF and OLC "pentanaphthoates" were identical but differed from that of ouabain 2', 3', 4', 1, 19-pentanaphthoate. To determine the nature of the HIF/OLC naphthoates with extremely weak or nil CD, exciton coupled CD for all fifteen ouabain pentanaphthoates carrying a-L-rhamnose at C-1, 19,11, and 5 were calculated; nine pentanaphthoates with rhamnose trisnaphthoates at these carbons were also prepared. Although calculated and experimental values gave overall good agreements, none showed the anticipated weak CD splitting. Availability of BION HIF allowed preparation of naphthoates from 8 ug of sample giving three to four pentanaphthoates, three tetranaphthoates (all with positive couplet) as well as the original "pentanaphthoates" peak that exhibited the weak or nil CD. Surprisingly, however, the so-called "pentanaphthoate" peak was not a pentanaphthoate. CD analysis of other HPLC peaks and the microscale NMR of underivatized HIF suggested a plausible, but very unusual candidate for the nature of "HIF", This is being further investigated.

Plant and Vertebrate Cannabinoid Agonists: Medicinal Uses
By Prof. R. Mechoulam, Hebrew University
　Cannabis sativa was one of the first plants used in medicine. Its use continued over millennia in various countries to treat arthritis, stimulate the appetite, prevent haemorrhage and pain in childbirth, as an antiemetic, and against migraine while in combination with other herbs for rheumatic pains, disorders of the female reproductive tract, malaria, and beri-beri. With our identification of A-THC as the main active constituent in Cannabis In 1964, some of these activities were confirmed. THC is used officially as an antiemetic in cancer chemotherapy and as appetite stimulation in AIDS, Although application is limited due to psychotropic side effects. However, It is used with considerable success in pediatric oncology to prevent vomiting caused by anticancer drugs as THC side effects are not seen in children. Other activities being explored include antiinflammatory activity in multiple sclerosis; and glaucoma. Cannabidiol has been shown to have antianxiety, antiepileptic and possibly antipsychotic properties. However does are high (above 1 gr/day) and more efficient derivative are being explored. In 1992-1995, we reported discovery of arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-Ara-Gl) in brain and gut respectively, which bind to the cannabinoid receptors in the brain and the periphery and parallel THC in many activities. Thus anandamide and 2-Ara-Gl administrated i.p. in mice, caused lowering of activity in an immobility and an open field test and produced hypothermia and analgesia. These effects are identical to those of psychotropic cannabinoids except that anandamide and 2-Ara-Gl potencies are lower and act faster. The activities of 2-Ara-Gl is potentiated in vitro and in vivo by chemically closely related constituents which by themselves are inactive. Anandamide inhibits short-term memory and may also be a sleep factor. It has been shown to reduce blood pressure via peripheral mechanism. Anandamide is also present in the uterus in concentrations which vary during the monthly female cycle. HU-211 is being clinical tested as an antitrauma drug being an NMDA antagonist. It also inhibits TNF-a production and blocks blood-brain barrier destruction by certain microorganisms.

Interviews with Top Overseas Pharmacognosy Researchers
　The meeting was attended by specialists from multidisciplinary fields from around the world some of whom were interviewed as to their areas of interest, and future expectations of pharmacognosy.

Prof. Peter G. Waterman
　Prof. Peter G. Waterman, Director of Natural Product Programme, University of Strathclyde, Glasgow, U. K. described the drug discovery research conducted at his university as being slightly different from that of other research institutes in that they are focused on random screening and combines academic with considerable commercial research, the latter supporting the former. He feels it is vitally important to maintain and support areas with high biodiversity of plant species and suggests this can be achieved with a more concerted effort on the part of governments, industries and institutes by following the quid pro quo system practiced in Costa Rica and Madagascar.

Dr. Vincenzo De Luca
　Dr. Vincenzo De Luca of the Department de Sciences Biologiques, Universite de Montreal, Canada, whose research focuses on the Catharanthus roses from which chemotherapeutic agents can be synthesized, says that once the mechanism of how a plant produces a particular chemical is known, they are now able to engineer pathways to enhance the chemical properties of crop plants thanks to the advancement of gene knowledge. A focus of such research could be the increase of antioxidants in foods to enable people to continue with their normal diet but in a healthier manner. Concerning the Symposium, he hopes that he can point out the advantages of molecular biology in the more traditional areas of pharmacognosy through his lecture and so open up an opportunity for collaborative research.

Dr. Raymond Ketchum
　Dr. Raymond Ketchum of the Institute of Biological Chemistry Washington State University, the U. S. A., notes that natural products and their derivatives have only recently been elevated from the realms of home medication and shaminism when Taxol, a very powerful cancer drug found in the U. S., received nationwide media coverage. Ever since, there has been an increasing awareness and interest in them, prompting researches. Although synthesis of chemicals has been achieved, neccesitated by the limited supply of sources, the yields are too low to be commercially viable. Besides which, nature does a better job of synthesizing chemicals. There is a need therefore for biological methods of production from plants or in cell cultures derived from them, which is the focus of his lecture at the Symposium. He is also most enthusiastic of the new discoveries being made of plant species at biodiverse preserves in the States which holds promise of opening up further areas of research.