Graviola is a small, upright evergreen tree growing 5 to 6 meters in height with large dark green and glossy leaves. It is indigenous to most of the warmest tropical areas in South and North America including the Amazon. It produces a large heart-shaped edible fruit that is 6-9", yellow green in color, with white flesh. The fruit is sold in local markets in the tropics where it is called Guanabana or Brazilian Cherimoya and is excellent for making drinks and sherbets and, though slightly sour-acid, can be eaten out-of-hand.

All parts of the Graviola tree are used in natural medicine in the tropics including the bark, leaves, roots, fruit and fruit-seeds. Different properties and uses are attributed to the different parts of the tree. Generally the fruit and fruit juice is taken for worms and parasites, to cool fevers, to increase mother's milk after childbirth (lactagogue), and as an astringent for diarrhea and dysentery. The crushed seeds are used as a vermifuge and anthelmintic against internal and external parasites and worms. The bark, leaves and roots are considered sedative, antispasmodic, hypotensive and nervine and a tea is made for various disorders for those purposes.

Graviola has a long rich history of use in herbal medicine as well as a long recorded indigenous use. In the Peruvian Andes, a leaf tea is used for catarrh and the crushed seed is used to kill parasites In the Peruvian Amazon the bark roots and leaves are used for diabetes and as a sedative and antispasmodic. Indigenous tribes in Guyana use a leaf and/or bark tea of Graviola as a sedative and heart tonic. In the Brazilian Amazon, a leaf tea is used for liver problems and the oil of the leaves and unripe fruit is mixed with olive oil and used externally for neuralgia, rheumatism and arthritis pain. In Jamaica, Haiti and the West Indies, the fruit and/or fruit juice is used for fevers, parasites, as a lactagogue, and diarrhea; and the bark or leaves are used as an antispasmodic, sedative, and nervine for heart conditions, coughs, grippe, difficult childbirth, asthma, asthenia, hypertension and parasites.

Many bioactive compounds and phytochemicals have been found in Graviola as scientists have been studying its properties since the 1940's. Its many uses in natural medicine has been validated by this scientific research. The earliest studies were between 1941 and 1962. Several studies by different researchers demonstrated that the bark as well as the leaves had hypotensive, antispasmodic, vasodilator, smooth muscle relaxant and cardiodepressant activities in animals. Researchers re-verified Graviola leaf's hypotensive properties in rats again in 1991. Several studies over the years have demonstrated that leaf, bark, root, stem and seed extracts of Graviola are antibacterial in vitro against numerous pathogens and that the bark has antifungal properties. Graviola seeds demonstrated active antiparasitic properties in a 1991 study, and a leaf extract showed to be active against malaria in two other studies in 1990 and 1993. The leaves, root, and seeds of Graviola demonstrated insecticidal properties with the seed demonstrating strong insecticidal activity in a early 1940 study. In a new 1997 clinical study, novel alkaloids were found in Graviola fruit with anti-depressive effects in animals.

In an 1976 plant screening program by the National Cancer Institute, the leaves and stem of Graviola showed active cytotoxicity against cancer cells and researchers have been following up on this research ever since. Much of the research on Graviola focuses on a novel set of phytochemicals called annonaceous acetogenins. The potent antitumor, pesticidal and/or insect antifeedant properties of these annonaceous acetogenins have been reported and patented. Graviola produces these natural compounds in leaf, bark and twig tissues, and they have be documented to possess both highly anti-tumor and pesticidal properties.

Mode of action studies in three separate laboratories have recently determined that acetogenins are superb inhibitors of Complex I in mitochondrial electron transport systems from several organisms including tumors. Research on various Annona species of plants has yielded many extremely potent acetogenins. Many of them have cytotoxicity with ED50 values as low as 10-9 ug/ml. Active compounds from Graviola and other Annona plants have been submitted to the NIH anti-AIDS screen by Purdue University and their work is continuing with a number of other active plant species in the Annona plant family. Thus far, Purdue and/or it's staff have filed at least 9 US and/or international patents on their work around the antitumorous and insecticidal properties and uses of these acetogenins.

Three separate research groups have isolated novel compounds in the seeds and leaves of Graviola which have demonstrated significant anti-tumorous, anticancerous and selective toxicity against various types of cancer cells, publishing 8 clinical studies on their findings. One study demonstrated that an acetogenin in Graviola was selectively cytotoxic to colon adenocarcinoma cells in which it was 10,000 times the potency of adriamycin (a chemotherapy drug). Cancer research is ongoing on Graviola, and four new studies have been published in 1998 which further narrow down the specific phytochemicals which are demonstrating the strongest anticancerous and antiviral properties.

Annonaceous acetogenins are only found in the Annonaceae family. In general, various annonaceous acetogenins have been documented with antitumor, antiparasitic, pesticidal, antiprotozoal, antifeedant, anthelmintic, and antimicrobial activities. There has been much interest in the chemicals which have demonstrated potent antitumor properties and several research groups are trying to synthesize these chemicals for new chemotherapeutic drugs. In a review of these natural chemicals in The Journal of Natural Products in 1999 they noted: "The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms."

Another review in the Skaggs Scientific Report 1997-1998 states, "Annonaceous acetogenins, particularly those with adjacent bis-tetrahydrofuran (THF) rings, have remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal, and antifeedant activities. Many of these fatty acid derivatives have similar carbon skeletons; their striking diversity originates mainly from the relative and absolute configuration of their various stereogenic oxygen functions."

Purdue University has conducted a great deal of research on annonaceaous acetogenins, much of which has been funded by The National Cancer Institute and/or the National Institute of Health. In one of their reviews titled Recent Advances in Annonaceous Acetogenins, they state: "Annonaceous acetogenins are waxy substances consisting of C32 or C34 long chain fatty acids which have been combined with a 2-propanol unit at C-2 to form a lactone. They are only found in several genera of the plant family, Annonaceae. Their diverse bioactivities as antitumor, immunosuppressive, pesticidal, antiprotozoal, antifeedant, anthelmintic, and antimicrobial agents, have attracted more and more interest worldwide. Recently, we reported that the Annonaceous acetogenins can selectively inhibit the growth of cancerous cells and also inhibit the growth of adriamycin resistant tumor cells. As more acetogenins have been isolated and additional cytotoxicity assays have been conducted, we have noticed that, although most of acetogenins have high potencies among several solid human tumor cell lines, some of the derivatives within the different structural types and some positional isomers showed remarkable selectivity's among certain cell lines, e.g., against prostate cancer (PC-3). We now understand the primary modes of action for the acetogenins. They are potent inhibitors of NADH: ubiquinone oxidoreductase, which is in an essential enzyme in complex I leading to oxidative phosphorylation in mitochondria. A recent report showed that they act directly at the ubiquinone-catalytic site(s) within complex I and in microbial glucose dehydrogenase. They also inhibit the ubiquinone-linked NADH oxidase that is peculiar to the plasma membranes of cancerous cells."

In 1997, Purdue University published information with promising news that several of the annona acetogenins "not only are effective in killing tumors that have proven resistant to anti-cancer agents, but also seem to have a special affinity for such resistant cells." In several interviews after this information was publicized, Purdue pharmacologist Dr. Jerry McLaughlin, the lead researcher in most of Purdue's studies on the Annona chemicals, says cancer cells that survive chemotherapy may develop resistance to the agent originally used against them as well as to other, even unrelated, drugs. "The term multi-drug resistance (MDR) has been applied to this phenomenon," McLaughlin says. He explains that such resistance develops in a small percentage of cancer cells when they develop a "P-glycoprotein mediated pump" capable of pushing anti-cancer agents out of the cell before they can kill it. Normal cells seldom develop such a pump.

"If having this pump was such a good deal, all cells would have it. But all cells don't," McLaughlin says in a statement from Purdue. "In a given population of cancer cells in a person, maybe only 2% of the cancer cells possess this pump. But it's those 2% of cancer cells that eventually grow and expand to create drug-resistant tumors." McLaughlin and his colleagues say some studies have tried to bypass these pumps by keeping them busy with massive doses of other drugs, like the blood pressure agent verapamil. In this way, it was hoped that some of the anti-cancer drugs would enter the cell and destroy it. But this only caused potentially fatal side effects such as loss of blood pressure.

In the June issue of Cancer Letters, the Purdue researchers reported that the annona acetogenin, bullatacin, preferentially killed multi-drug resistant cancer cells because it blocked production of adenosine triphosphate, ATP, the chief energy-carrying compound in the body. "A multi-drug resistant cell requires a tremendous amount of energy to run the pump and extrude things out of the cell," McLaughlin says. "By inhibiting ATP production, we're essentially pulling the plug on its energy source." But what about the effect on ATP in normal cells? "Normal cells and standard cancer cells may be able to minimize the effect of this compound because they don't require vast amounts of energy needed by the pump-running cells," the Purdue researcher says. "The resistant cell is using its extra energy for this pump as well as to grow, so it is really taxed for energy. When we mess with the energy supply, it kills the cell."

In the June issue of the Journal of Medicinal Chemistry, McLaughlin and his colleagues described a study of 14 Annona compounds that seem to be potent ATP blockers. "This study tells us how to maximize this activity, so we have a pretty good idea what compounds we'd like to try in animals with multi-drug resistant tumors," he says.

While the latest research on Graviola has focused on its cancer-fighting effect it is interesting to note that medicine men in South America have used it for centuries to treat an astonishing number of ailments.

Country	Ethnobotany: Worldwide Uses
Bahamas	Chill, Fever, Flu, Nervousness, Palpitation, Rash, Sedative, Skin Disease
Brazil	Analgesic, Fever, Neuralgia, Parasites, Rheumatism
Curacao	Childbirth, Gall-Bladder, Nervousness, Parturition Sedative, Tea, Tranquilizer
Elsewhere	Analgesic, Arthritis, Asthma, Astringent, Antiphlogistic, Dysentery, Febrifuge, Insecticide,Cyanogenetic, Kidney, Lactagogue, Malaria, Pectoral, Pediculicide, Piscicide, Scurvy, Stomach
Haiti	Asthenia, Cataplasm, Cicatrizant, Cough, Diarrhea, Emetic, Grippe, Pediculicide, Pellagra, Soporific, Sore, Spasm, Stomachic
Jamaica	Antispasmodic, Diuretic, Fevers, Lactagogue, Vermifuge
Malaya	Boil, Cough, Dermatosis, Rheumatism
Mexico	Astringent, Diarrhea, Dysentery, Fever, Liqueur, Pectoral, Ringworm, Scurvy
Panama	Anthelmintic, Diarrhea, Dyspepsia, Internulcer, Kidney, Piscicide, Ulcer(stomach), Vermifuge
Trinidad	Depurative , Fainting, Flu, Hypertension, Glactagogue, High Blood Pressure, Insomnia, Palpitation, Ringworms
Venezuela	Bilious, Diarrhea
West Indies	Childbirth, Diarrhea, Hypertension, Lactagogue, Worms

This information was reprinted with permission from the Raintree Tropical Plant Database:  http://www.rain-tree.com/plants.htm

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>> NOTE: Each serving of Ellagic Insurance Formula contains 600mg pf Graviola