From shaman to human clinical trials: the role of industry in ethnobotany, conservation and community reciprocity.

Shaman Pharmaceuticals is a development-stage company engaged in developing traditional pharmaceuticals identified through a discovery process focused on isolating active compounds from tropical plants with a history of medicinal use. This process has resulted in two products in clinical trials: Provir, an oral product for the treatment of respiratory viral infections, and Virend, a topical antiviral product for the treatment of herpes. Shaman's drug-discovery process targets specific plants that have been used for medicinal purposes by native peoples. By integrating the sciences of ethnobotany, medicine and plant natural product chemistry, Shaman has been able to achieve time and cost savings for the identification of active compounds and preclinical development of its initial products. Numerous drugs have entered the international pharmacopoeia via the study of ethnobotany and traditional medicine. Two important elements of this approach to drug discovery are the percentage of plants that show activity against specific viral pathogens and the correlation between the folk therapeutic classification of plants used and the percentage of those plants that have shown activity in our antiviral screens. Conservation and direct reciprocity to indigenous communities are important features of Shaman Pharmaceuticals' drug-discovery process.

SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago).

SP-303, a large proanthocyanidin oligomer isolated from the latex of the plant species Croton lechleri (Eupborbiaceae) has demonstrated broad activity against a variety of DNA and RNA viruses. In cell culture, SP-303 exhibits potent activity against isolates and laboratory strains of respiratory syncytial virus (RSV), influenza A virus (FLU-A) and parainfluenza virus (PIV). Parallel assays of SP-303 and ribavirin showed comparable activity against these viruses. SP-303 also exhibits significant inhibitory activity against herpesvirus (HSV) types 1 and 2, including herpesviruses resistant to acyclovir and foscarnet. Inhibition was also observed against hepatitis A and B viruses. The antiviral mechanism of SP-303 seems to derive from its direct binding to components of the viral envelope, resulting in inhibition of viral attachment and penetration of the plasma membrane. Antiviral effects of SP-303 were measured by three distinct methods: CPE, MTT and precursor uptake/incorporation. Cytotoxicity endpoints were markedly greater than the respective antiviral endpoints. SP-303 exhibited activity in RSV-infected cotton rats and African green monkeys, PIV-3-infected cotton rats, HSV-2 infected mice and guinea pigs and FLU-A-infected mice. The most successful routes of SP-303 administration for producing efficacy were: topical application to HSV-2- genital lesions in mice and guinea pigs, aerosol inhalation to FLU-A-infected mice and PIV-3-infected cotton rats, and oral dosage to RSV-infected cotton rats. A variety of toxicological evaluations demonstrated the safety of SP-303, particularly orally, which was predictable, since condensed tannins are a common dietary component. It is notable that the larger proanthocyanidins as a class have high antiviral activity, whereas most of the monomers are inactive. Clinical trials are ongoing to evaluate SP-303 as a therapeutic antiviral agent.

Auriculatin 4'-O-Glucoside: A New Prenylated Isoflavone Glycoside from Erythrina eriotricha1.

In addition to known compounds, sigmoidin C and 8-(3,3-dimethylallyl)-erythrinin C, also called senegalensin, a new isoflavone glycoside designated auriculatin 4'- O-glucoside was isolated from the chloroform extract of the stem bark of ERYTHRINA ERIOTRICHA. Its structure was elucidated as 7,6-(2''',2'''-dimethyl-2 H-pyrano)-2',5-dihydroxy-8-(3,3-dimethylallyl)-isoflavone 4'- O-beta- D-glucoside on the basis of spectroscopic methods and chemical evidence.

A new prenylated isoflavone and long chain esters from two Erythrina species.

Two new compounds, a long chain ester 1 of p-coumaric acid and a prenylated isoflavone, senegalensin [5], 5,4'-dihydroxy-8-(gamma,gamma-dimethylallyl)-[5"-(hydroxyisopropyl ) (2",3":6.7)] isoflavone, in addition to a known long chain ester 2 of ferulic acid, have been isolated and characterized from the stem bark of the Cameroonian medicinal plant Erythrina senegalensis. Another known compound 3, a long chain ester of ferulic acid, was isolated from Erythrina excelsa. The structures of all the compounds were determined by spectroscopic techniques.

A new prenylated isoflavone and triterpenoids from Erythrina eriotriocha.

In addition to known triterpenoids maniladiol [6] and serrat-14-ene-3 beta,21 alpha-diol [7], two new compounds, one oleanane derivative designated as 28-acetoxyerythrodiol [1] and one isoflavone designated as 5,4'-dimethoxy-3'-prenylbiochanin A [5], have been isolated and characterized from the CHCl3 extract of the stem bark of Erythrina eriotriocha. Their structures have been established on the basis of the spectrocopic techniques (ir, nmr, uv, ms) and chemical evidence.

Hypoglycaemic activity of dioscoretine from tubers of Dioscorea dumetorum in normal and alloxan diabetic rabbits.

Dioscoretine isolated from the aqueous fraction of the methanol extract of Dioscorea dumetorum tubers when administered intra-peritoneally to normal and alloxan diabetic rabbits produces significant hypoglycaemic effects at a dose of 20 mg/kg. The fasting blood sugar in normoglycaemic rabbits was reduced from 112 mg/100 ml to 55 mg/100 ml after 4 hours. In alloxan diabetic rabbits, the blood sugar was lowered from 520 mg/100 ml to 286 mg/100 ml at the same time interval. The aqueous fraction of the methanol extract produced comparable effects at 100 mg/kg. The chloroform fraction of the same extract raised the fasting blood sugar of normal rabbits to 196 mg/100 ml after 6 h. The acute toxicity studies gave LD50 values of 1.4 g/kg for the aqueous fraction and 0.58 g/kg for dioscoretine when tested on mice. The hypoglycaemic effects were compared to those of tolbutamide.

Antidiabetic and aldose reductase activities of biflavanones of Garcinia kola.

Kolaviron, a mixture of C-3/C-8 linked biflavonoids obtained from Garcinia kola produces significant hypoglycaemic effects when administered intraperitoneally to normal and alloxan diabetic rabbits at a dose of 100 mg kg-1. The fasting blood sugar in normoglycaemic rabbits was reduced from 115 mg/100 mL to 65 mg/100 mL after 4 h. In alloxan diabetic rabbits, the blood sugar was lowered from 506 mg/100 mL to 285 mg/100 mL at 12 h. The hypoglycaemic effects have been compared with those of tolbutamide. Kolaviron inhibited rat lens aldose reductase (RLAR) activity, with an IC50 value of 5.4 x 10(-6). The significance of these findings in the potential use of kolaviron as an antidiabetic agent is discussed.

Extractives from Erythrina eriotriocha.

From the stem bark of Erythrina eriotriocha, a novel isoflavone, eriotriochin has been isolated and characterized, in addition to known compounds auriculatin, dihydroauriculatin, and 3'-O-methylorobol. The structure of compound 1 was determined by COSY, selective INEPT, 2D HMBC, NOESY, DEPT, and other spectroscopic techniques.

Sigmoidin F, a new prenylated flavonoid from Erythrina sigmoidea.

Sigmoidin F, a new prenylated flavanone, as well as abyssinone IV and 5,7,4'-trihydroxy-3'-methoxy-5'-(1"-prenyl) flavonone have been isolated from the stem and bark of Erythrina sigmoidea. The structure of 1 has been confirmed by a combination of 1H-nmr and other spectroscopic techniques.

Two new flavonoids from Erythrina eriotriocha.

In addition to the known compounds erythinasinate [1] and abyssinone V [2], two new flavonoids were isolated from the CHCl3 extract of the stem bark of Erythrina eriotriocha and characterized by spectroscopic techniques as 3'-prenylnaringenin [3] and 2'-hydroxy-5'-methoxybiochanin A [4].

Isolation and characterization of taxifolin 6-C-glucoside from Garcinia epunctata.

Garcinia epuctata is an indigenous medicinal plant of Cameroon from which taxifolin 6-C-glucoside was isolated and characterized. The nmr assignments obtained from COSY and INAPT experiments are reported for the first time.

A new diterpene from Cupressus goveniana var. abramasiana: 5 beta-hydroxy-6-oxasugiol (cupresol).

The petroleum ether-EtOH extract of Cupressus goveniana var. abramasiana (Cupressaceae) yielded sugiol (1) and the new diterpene, cupresol (5 beta-hydroxy-6-oxasugiol), for which structure 2 was established by spectroscopic and chemical means.