Is the Answer to HIV-Associated Diarrhea Found in South America’s Rain Forest?
By Nelson Vergel, BsChE, MBA

As more and more shamans (traditional healers) in the Amazonian rain forest die as they age, the new generations of indigenous people are moving on to jobs in cities, forgetting valuable medicinal knowledge gathered through centuries. Recognizing this potential loss in key know-how a small team from a company called Shaman Pharmaceuticals in South San Francisco went searching for medicinal plants in South America’s rain forest by working hand-in-hand with local shamans. With the help of ethnobotanists and physicians who worked with the traditional healers to document the therapeutic qualities of the foliage, Shaman Pharmaceuticals created a library of 2,600 medicinal plants.

“Indigenous people led us to a situation where we could make and improve a safe and effective pharmaceutical product and give back to the population that provided the information,” said Lisa Conte, founder of Shaman.

“We ensure that medicinal plants are cultivated with replanting that requires careful management and conservation in conjunction with the indigenous and local peoples who reside in the forest where it grows,” added Steven King, PhD, Vice President of Sustainable Supply, Ethnobotanical Research and Intellectual Property, one of the main experts involved in the search for medicinal plants in South America.

One of their earliest targets was Sangre de Drago ( “Dragon’s blood” or Croton lechleri), a plant with a blood-like sap (properly called ‘latex’) that has been used by indigenous people for centuries to treat wounds, diarrhea, stomach problems, and other ailments (Jones 2003.) Shaman’s researchers isolated and purified the main component from the latex, named “crofelemer”, and formulated crofelemer into standard oral medication. The company produced a supplement called “Normal Stool Formula” that was widely used in the HIV community in the 1990s to successfully treat diarrhea.

“It was our best seller for diarrhea,” said Fred Walters, founding director of the Houston Buyers Club, a Houston-based non profit that provides supplements at cost to people with HIV nationwide. “We were sad to see Shaman close its doors due to financial difficulties back then, so we are glad to see Napo Pharmaceuticals acquiring the rights for the pharmaceutical-grade of the product for new research and potential FDA approval,” added Mr. Walters.

“In our country and most other western countries, there are only two anti-diarrhea medications, both approved over 30 years ago and both work about the same way – they slow or stop the movement of the gut. Crofelemer works differently and we see an exciting opportunity to study crofelemer for HIV-associated diarrhea and many other diseases where diarrhea is a major, sometimes fatal symptom of other infections,” said David Golman, PharmD, Senior Director of Clinical Operations of Napo Pharmaceuticals. An estimate by the World Health Organization suggests that worldwide, everyday 6,800 children die from diarrhea and its complications (Guerrant 2002.) “Clearly, there is the need for a more effective and widely available treatment for diarrhea,” added Dr. Golman

Diarrhea associated with HIV infection is still very much an issue to many. In a survey performed by POZ magazine in September 2007 with a total of 941 responders, 21 % said that side effects were the primary reason that they switched antiretroviral regimens in the past. Diarrhea, nausea and vomiting were the number one side effects that make a person switch meds. In a recent prospective study of 163 HIV+ patients performed by Dr. Uzma Siddiqui, 28.2% of patients reported having 3 or more bowel movements per day but only 14.1% reported use of anti-diarrheal medications (about ½ of those with chronic diarrhea) (Siddiqui 2007).

Before the widespread availability of highly active antiretroviral therapy (HAART) in 1995, most HIV-infected people developed progressive immuno-supression and opportunistic infections (OIs); and many OIs were in the gastrointestinal track causing diarrhea. After the introduction of HAART, there was a dramatic decrease of OI-associated diarrhea, however, non-infectious causes appear to have become more dominant. In a review performed by Stephanie Call, MD (Call 2000) it was shown that between 1995 and 1997, while the use of HAART increased, non-infectious causes of diarrhea increased from 32% to 70%. One prominent cause of non-infectious diarrhea among HAART- treated patients is the antiretroviral medications themselves. Since their introduction in the market, we have learned that protease inhibitors like Viracept®, Norvir®, Kaletra®, Aptivus®, Lexiva®, Prezista®, and others can cause significant, even serious gastrointestinal problems in people taking those medications (Physicians Desk Reference 2008).

Another potential cause of HIV-associated diarrhea is the virus itself. In an interview for the newsletter HIVhealth, Calvin Cohen, MD, Research Director of the Community Research Initiative of New England, said that the HIV virus itself can increase the risk of diarrhea since HIV attacks the lymph nodes in the intestines. This may lead to a condition called enteropathy which can result in diarrhea and other diarrhea symptoms.

Currently, there are no drugs approved by the FDA for HIV-associated diarrhea in the U.S. but it remains a serious problem for many people. “Chronic diarrhea not only has a significant negative impact on quality of life, but it can also affect HIV treatment and adherence, decreasing the effectiveness of medications,” said Shannon Schrader, MD, a leading physician in Houston. “Diarrhea may also lead some of us to switch their patients to other HIV medications, reducing treatment options later on when the patient might need them more,” added Dr. Schrader.

“I have lived with HIV for over 15 years and deal with diarrhea weekly, even though my immune system has improved with HIV medicines,” said Al Benson, a patient and activist living in Los Angeles. “I am glad we have drugs like Imodium® and Lomotil®, but I am concerned that they give me a yo-yo effect from constipation to diarrhea returning with a vengeance. I certainly believe that we need another option that is more gentle on the gut,” added Mr. Benson.

Crofelemer is believed to work by a different mechanism of action. The common anti-diarrheal drugs such as Imodium® and Lomotil® are absorbed into the blood, distribute throughout the body, and work by slowing down the flow of material through the intestines, they are called “anti-motility” drugs. While this stops diarrhea, it also allows toxins to remain in the body longer. Crofelemer is thought to act locally in the gut, and because it is not absorbed the potential for systemic adverse drug effects and interactions are minimized. Crofelemer does not affect motility; instead it reduces the abnormal excessive flow of water into the gut that is the root cause of many diarrheas. In clinical studies crofelemer has been very well tolerated, and constipation in particular has not been commonly reported (Napo Pharmaceuticals, data on file).

“Crofelemer works by normalizing water flow in the gut. It is not absorbed into the blood, but acts in the intestines to treat diarrhea and reduce the chances for dehydration. Because it is not absorbed and acts locally, it has a favorable safety profile,” explained Pravin Chaturvedi, PhD, Chief Scientific Officer of Napo. The drug’s capacity to treat diarrhea by blocking the secretion of chloride ions, and still allowing bowel movements, makes this useful for treating chronic diarrhea,” explained Dr. Chaturvedi. “This is a novel mechanism of action for the treatment and management of diarrhea, and it has been brought to us by indigenous knowledge,” added Dr. Chaturvedi.

A study published in 2004 found that Viracept®, a commonly used protease inhibitor used to treat HIV, stimulated chloride ion secretion and may explain its high rates of diarrhea in HIV-positive patients (Rufo 2004). Crofelemer’s mechanism of action could provide an answer to drug induced secretory diarrhea.

Crofelemer has been tested in clinical studies involving approximately 1,700 patients with diarrhea of various causes. Its novel mechanism is important to people living with chronic diarrhea, so much so, that the U.S. Food and Drug Administration (FDA) granted Napo a fast-track designation for the crofelemer drug for use in treating HIV-related diarrhea (Napo Pharmaceuticals, data on file.) Napo is currently conducting a clinical study in HIV positive individuals with chronic diarrhea. More information can be found on the company’s web site (


Call, S. et al. The Changing Etiology of Chronic Diarrhea in HIV-infected Patients with CD4 Cell Counts Less Than 200 cells/cc. The American Journal of Gastroenterology 2000; Volume 95 (11): 3142-3146.
Guerrant, R. et al. Magnitude and Impact of Diarrheal Diseases. Archives of Medical Research 2002; Volume 33 (4): 351-355.

Jones, K. Review of Sangre de Drago (Croton lecheri)- A South American Tree Sap in the Treatment of Diarrhea, Inflammation, Insect Bites, Viral Infections, and Wounds: Traditional Uses to Clinical Research. The Journal of Alternative and Complementary Medicine 2003; Volume 9 (6); 877-896.

Rufo, PA. et al. Diarrhea-associated HIV-1 Aspartyl Protease-inhibitors Potentiate Muscarinic Cl- Secretion by T84 cells Via Prolongation of Cytosolic Ca2+ Signaling. Am J Physiol Cell Physiol 2004; Volume 286: 998-1008.

Siddiqui, U. et al. Prevalence and Impact of Diarrhea on Health-related Quality of Life in HIV-infected Patients in the Era of Highly Active Antiretroviral Therapy. Journal of Clinical Gastroenterology 2007; Volume 41 (5); 484-490.

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