Our Project, in order to provide incentive as well as funding, needs a monetary impulse. Medecine in the rainforest, from the rainforest is a major wellspring from which we can draw resources and interest from. Viral diseases, including emerging and chronic viruses, are an increasing worldwide health concern. As a consequence, the discovery of new antiviral agents from plants has assumed more urgency than in the past. A number of native Amazonian medicines of plant origin are known to have antimicrobial and anti-inflammatory activity, although only a few have been studied for their antiviral properties and immunomodulating effects.Co-evolution between plants and their natural enemies including insects, bacteria, fungi, nematodes, animals, humans, and viruses is considerably more far reaching than current theories of reciprocal interactions suggest. Counter-resistance, genetic adaptability, polymorphic immune capacity, and pleomorphism among microbial agents allow for immense diversity of species and endless biochemical possibilities. It is that richness we will capitalize upon, in order to promote a use and reason for our research in the forest.In order to adapt to environmental insults, plants produce a vast number of natural products that have antimicrobial and immunomodulating potential. These include isoflavonoids, indoles, phytosterols, polysaccharides, sesquiterpenes, alkaloids, glucans, tannins, a variety of vitamins and trace minerals that function as antioxidants and co-enzymes, and many other phytochemical substances. In addition, there are a number of parallels between plant immunological activity and the immune systems of mammals, including adaptive mechanisms for viral resistance. The Amazonian region is among the earth's richest zones of biodiversity. It includes plants, animals, insects, as well as microbial organisms, and is one of nature's perfect evolutionary laboratories for plant biology.

There are two ways natural products are selected for investigation. The classical method is laboratory based and relies on previous taxonomic findings, phytochemical factors, immunopharmacological studies, and random screening methods. The other, which is gaining popularity among investigators, is searching traditional texts and herbal medicine usage, including oral interviews with traditional indigenous healers the ethnobotanical routeIn one study, researchers found that an ethnobotanically driven approach led to a higher percentage of active compounds isolated than the standard high volume random screening method, reporting a 125-630 times more effective yield depending on the type of virus.

Largely due to the AIDS epidemic, an imperative for developing effective antivirals has generated considerable activity in anti- viral screening during the last two decades. However, the search for antiviral compounds has not been easy. Relatively few antiviral drugs are available, and those approved for use often have high side-effect profiles and exhibit the potential to cause rapid resistance among targeted viral strains. An antiviral must meet three criteria: (1) it must inhibit the virus completely without affecting the host cells, (2) it must have a broad range of activity, and (3) it must not be immunosuppressive

A number of plant substances have been found to meet the basic criteria, and screenings have been performed on several thousand plant extracts and other natural products.hree have been well studied: Croton lechleri, Phyllanthus niruri, and Uncaria tomentosa. Among these, Croton and Phyllanthus have received more attention than Uncaria for their antiviral properties. Extensive research has been conducted on Curcuma, primarily for its anti-inflammatory effects and on inhibition of HIV, although primarily with species found in India
and China. Mangifera has been studied for its anti-inflammatory, and antiviral activity against herpes simples II virus, although primarily with Cuban, Chinese, or Indian species. Although considered to have antiviral activity and extensively used for ceremonial purposes among Amazonian healers, few studies have been performed on the antiviral properties of the tobacco plant, Nicotiana tabacum.

Immunomodulating activity refers to biological or pharmacological effects of compounds on humoral or cellular aspects of the immune response. The human immune response is a highly complex and extraordinarily sophisticated system involving both innate and adaptive mechanisms Studies of how plant substances affect immune response employ mechanistic bioassay methodologies. Basic research on natural substances with immunomodulating properties is performed by assays primarily carried out on the stimulation of nonspecific immunity of the innate response, such as the efficiency of granulocytes, macrophages, complement, and natural killer cells, and their effects on phagocytosis, lymphocyte proliferation, and T-lymphocyte migration macrophage activation by beta-1,3-D-glucan. More recent research on immunomodulating substances includes studies on cytokine production by macrophages such as interleukin-1 (IL-1),` interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a).

Plants from tropical rainforests represent a rich source of potential immunomodulating substances and leads from ethnobotanical practices have been the primary source of plant selection in recent years

Sangre de Grado (Croton lechleri)

Croton lechleri is a large tree that grows in the upper Amazon region of Colombia, Ecuador, and Peru where the majority of the field research has taken place. A dark red resin, from which the name sangre de grado derives, flows easily from cuts in the bark and is used fresh or processed into a powdered dry extract of the resin for medicinal purposes. In traditional Amazonian medicine sangre de grado is used as an oral gargle for sore throat, as a vaginal antiseptic after childbirth, topically as a hemostatic, and taken internally for wound healing. It is also used to improve gastrointestinal function, to protect the mucous membrane lining of the lower gastrointestinal tract, and to treat diarrhea. There is only one comprehensive review of the research and literature and two randomized controlled trials in human subjects have been performed on extracts of sangre de grado.

The known chemical composition of sangre de grado includes a considerable number of compounds including several simple phenols and diterpenes, proanthocyanidins, phytosterols, a ihydrobenzofuran lignan, and the alkaloid taspine. The pharmacological actions of sangre de grado include anti-oxidant potential, anti-inflammatory effects, anti-bacterial activity, antitumor potential, anti-diarrheal effects, wound healing, antifungal effects, and antiviral properties. In at least one study, its phenolic and diterpene compounds demonstrated potent antibacterial activity against Bacillus subtilis and Escherichia coli. In a study designed to evaluate its gastrointestinal effects, Miller et al concluded that, "sangre de grado is a potent, cost-effective treatment for gastrointestinal ulcers and distress via antimicrobial, anti-inflammatory, and sensory afferent-dependent actions." In the Chen study, antitumor properties were investigated in a Brazilian species (Croton cajucara) as well as an Ecuadorian species. The alkaloid taspine hydrochloride has been found to be the main cicatrizant or wound healing potential and a potential anticancer agent.

The anti-diarrheal action of sangre de grado has attracted the recent attention of researchers and several papers have been published on the mechanisms and effectiveness of this herb or diarrheal diseases. SP-303, a novel proanthocyanidin substance derived from the purified latex of Croton lechleri, has been shown to be effective in the treatment of persistent diarrhea associated with AIDS. One paper describes the results of a multi-center, phase II, randomized, double-blind, placebo-controlled study on 51 subjects using this substance over a period of four days. Patients in the SP-303 group experienced a statistically significant reduction in stool weight. An in vivo mouse study (treating cholera-toxin related secretory diarrhea), examining the mechanisms of the action of SP-303, showed that it has an inhibitory effect on cAMP-mediated chloride and fluid secretion.

Extracts of sangre de grado have been shown to have antiviral activity against influenza, parainfluenza, herpes simplex viruses I and II, and hepatitis A and B. In a multi-center, ouble-blind, placebo-controlled study, a topical preparation of SP-303 was used to treat recurrent genital herpes lesions in AIDS patients. Viral culture revealed 50 percent of the treated group and 19 percent of the placebo-treated patients became culture-negative at the end of the 21-day trial. Although immunomodulating properties of sangre de grado have not been specifically elucidated, it is feasible that its anti-inflammatory, antimicrobial, and antioxidant activity may provide non-specific immunomodulating effects as well.

There is a wide range of potential applications for sangre de grado, including as a broad-spectrum anti-diarrheal agent from causes such as side effects of drugs, chemotherapy or radiation treatment, microbial infections of the intestine, traveler's diarrhea, and viral-induced diarrhea as in AIDS. It may also have other uses in gastrointestinal disorders such as irritable bowel syndrome and ulcerative diseases. Its cytotoxic effects make it a possible antitumor agent and its cicatrizant properties provide wound-healing potential. In addition, the antimicrobial and anti-inflammatory effects of sangre de grado make it a useful compound in the clinical treatment of chronic viral diseases and as a natural antibacterial agent.

Uña de Gato (Uncaria tomentosa)

Uncaria tomentosa, or uña de gato (cat's claw), is the best known of the Peruvian medicinal plants and the most frequently represented in the literature. A woody vine containing a lear watery sap, it grows wild in the upper Amazon region of Peru and neighboring countries, and can reach several inches in diameter and 1,000 feet in height. The part used medicinally is the inner bark of the vine from which a boiled decoction is made or extracts produced. In recent years, extracts of the root have also been prepared commercially. Uña de gato is considered a sacred plant among the Ashaninkas and other indigenous Peruvian Amazonian tribes such as the Campo. According to the Austrian investigator Klaus Keplinger, the herb serves as a means of "regulating the physical and spiritual worlds" for these tribal groups.
The chemical composition of uña de gato includes 17 different alkaloids, quinovic acid glycosides, tannins, flavonoids, sterol fractions, and other compounds Indole alkaloids possess an indole ring in their structure, a versatile heterocyclic structure discovered in 1866, and found in a considerable number of medicinal products from plants The pharmacological actions of uña de gato include antioxidant properties, anti-inflammatory activity, immunomodulation, cytoprotection, antimutagenic properties, and antihypertensive effects, as well as ossible prevention of cerebral ischemia. Immunomodulating activity includes suppression of NF-kappa B, enhancement of B- and T-lymphocytes, stimulation of phagocytosis, and enhancement of IL-1 and IL-6. In a Peruvian study on rats, the investigators found that phagocytosis was increased when an extract was administered at a dose of 400 mg/kg. In a study by Sandoval et al a water extract showed cat's claw to be, "a remarkably potent inhibitor of TNF-a. The primary mechanism for cat's claw's anti-inflammatory action appears to be immunomodulation via suppression of TNF-a synthesis." A 1998 study showed that pentacyclic alkaloids weakly activated human B- and T-lymphocytes, and that tetracyclic oxindole alkaloids reduced the activity of pentacyclic oxindoles. In another recent study, Swedish researchers using an aqueous extract treated radiation-induced DNA damage in rats. Results indicated "significant" repair of DNA breaks. Based upon this research, it is generally accepted that the pentacyclic oxindole alkaloids are the principle immunomodulating agents in uña de gato.

Clinical Applications and Dosage

Uña de gato has broad therapeutic potential, including the treatment of chronic viral infections, viral and bacterial co-infections in AIDS, cancer, the prevention of radiation damage, nd in inflammatory disorders. Although there are no randomized controlled trials or published human outcome studies, some conditions reportedly improved by uña de gato include osteoarthritis, rheumatoid arthritis, rostatitis as a non-specific immuno-modulating agent in viral illnesses and cancer,81 and it may also have potential as an immunomodulating adaptogen in aging.

Although the field of study in immune enhancing compounds is relatively new, natural products from plants represent a rich and promising source of novel molecules with immunomodulating propertiesPlants are also a promising source of systemic broad-spectrum antivirals that may cause less damage to host cells infected by chronic viruses, such as hepatitis C, than do pharmaceuticals. Topical antiviral substances are also important areas of study for the treatment of viral lesions such as in herpes simplex virus, and plant-based substances offer promise as virucidals.The most promising of the currently known Amazonian herbs are Uncaria tomentosa and Croton lechleri, with Uncaria the more studied. Both plants have similar therapeutic properties, including anti-inflammatory, antiviral, antibacterial, antioxidant, and immunomodulating activity. By current investigations, the therapeutic differentiation between the two is that uña de gato appears to have more immune-stimulatory effects with sangre de grado demonstrating more antimicrobial activity. However, with a few exceptions, the majority of studies have been in vitro or in animal models, with weak to moderate immunomodulating and antiviral effects. There is no overwhelming evidence to support the public perception of these herbs as potent immune stimulants, although they appear to be beneficial and safe, non-specific immunomodulating botanicals

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James E. Williams, OMD