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
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James E. Williams, OMD