HerbalEGram: Volume 5, Number 7, July 2008

Napo Pharmaceuticals, Inc (Napo) is currently conducting a Phase 3 clinical trail on crofelemer for the treatment of diarrhea related to HIV.¹ Crofelemer is a large proanthocyanidin oligomer isolated from the latex (or tree sap). This purified chemically complex preparation is commonly known as sangre de drago “dragon’s blood” from the South American tree Croton lechleri, where it has been used for centuries by local healers in various maladies including diarrhea.²

According to the Napo Web site, the HIV(human immunodeficiency virus)-positive patients involved in this study will receive the drug twice a day and record their diarrhea-related symptoms. The study will last up to 6 months with 350 subjects (a number pre-agreed upon by the FDA) and involve participation from approximately 55 research facilities and clinics in the United States and Puerto Rico.

Diarrhea is prominent in patients with in HIV for 3 main reasons: the HIV virus itself can cause it by attacking lymph nodes in the gastrointestinal track, the immune suppression created by HIV increases the risks of other infections, and the conventional pharmaceutical drugs themselves taken to treat and suppress the HIV virus can cause diarrhea (e.g., protease inhibitors like Viracept®, Norvir®, Kaletra®, Aptivus®, Lexiva®, Prezista®). According to David Golman, PharmD, Senior Director of Clinical Operations at Napo the GI tract is also home of the largest amount of lymph node tissue anywhere in the body. HIV can easily infect these tissues. The HIV virus itself infects T-cells in the GI track, assimilates them, destroys them, and then replicates itself.³

Crofelemer has been shown repeatedly to have an anti-secretory mechanism of action which blocks chloride ions and subsequent water secretion. This keeps the gut from losing too much excess fluid, which is important since severe dehydration caused by diarrhea can cause death. Crofelemer is also not systemically absorbed into the body but remains in the gut giving it a higher level of efficacy than other treatments, and limiting the potential for adverse side effects. Most antidiarrheal agents paralyze or slow the gut causing constipation and cannot be taken for more than 24 hours. Such drugs include Imodium® (McNeil) and Lomotil® (Pfizer), the former of which is an over-the-counter (OTC) medication; their anti-motility properties only temporarily relieve symptoms of diarrhea.

Crofelemer has been tested on acute infectious diarrhea (also called traveler’s diarrhea) in a randomized, double-blind, placebo-controlled trial involving 184 patients from the US that had acquired their symptoms while traveling to Mexico or Jamaica.⁴ This study demonstrated that crofelemer was effective in reducing the duration of traveler’s diarrhea by 21 percent. In a more recent randomized, double blind, placebo-controlled inpatient study involving 98 Indian adult males and females with acute infectious diarrhea, crofelemer was statistically and significantly superior to placebo in both primary and secondary study endpoints.⁵ Overall clinical success was achieved in 79.1% of the evaluable patients receiving crofelemer compared to 28.2% of patients receiving placebo.

A multicenter, phase 2, randomized, double-blind, placebo-controlled study, evaluated the effect of crofelemer on patients with diarrhea related to AIDS.6 Subjects received 500 mg of crofelemer every 6 hours for 4 days and discontinued the use of any other antidiarrheal agents. The study demonstrated that crofelemer is safe, well-tolerated, and useful in reducing the weight and frequency of patients’ stools with AIDS-related diarrhea.

Results were also announced in a recent Napo release from a newly completed intent-to-treat analysis of existing data from two Phase 2 trials.⁷ These trials evaluated the effects of crofelemer in treatment of diarrhea-predominant irritable bowel syndrome (D-IBS). The results indicate that 500 mg of crofelemer twice a day improves the chance of having pain-free days in patients suffering from D-IBS.

Crofelemer is currently being tested in a Phase 2 clinical study for Vibrio cholerae-induced diarrhea at the International Center for Diarrheal Disease Research (ICDDR) in Dhaka, Bangladesh, with partial support from the US National Institute of Allergy and Infectious Disease (NIAID)  It is hoped that eventually crofelemer may help to decrease the mortality of severe child and infant diarrhea-related deaths, which is estimated by the World Health Organization (WHO) to be 6,800 children a day.⁸ So far the compound has demonstrated positive results in a cholera mouse model.⁹

More information about the company and current clinical trials is available at the Napo Pharmaceuticals Web site: www.napopharma.com/. Information about the crofelemer HIV-associated diarrhea study can be found at www.clinicaltrials.gov/, search term “crofelemer.” Patients interested in the HIV-associated study can pre-screen at www.ADVENTstudy.com/.

—Kelly E. Saxton

References

¹Vergel N. Is the answer to HIV-associated diarrhea found in South America’s rain forest? Medical News Today. April 15, 2008. Available at http://www.medicalnewstoday.com/articles/103933.php. Accessed June 30, 2008.
²Jones K, Review of Sangre de Drago (Croton lechleri) A South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: Traditional uses to clinical research. J Alt Compl Med. November 6, 2003;9(6):877-896.
³Douek D. HIV disease pathogenesis and the gastrointestinal tract. Paper presented at: 18^th Annual Clinical Care Options HIV Symposium; May 1-4, 2008; Rancho Mirage, CA.
⁴DiCesare D, DuPont HL, Mathewson JJ, Ashley D, Martinez-Sandoval F, Pennington JE, Porter SB. A double blind, randomized, placebo-controlled study of SP-303 (provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol. Oct 2002;97(10):2585-2588.
⁵Napo announces successful clinical results in Phase 2 study of crofelemer in acute adult infectious diarrhea [press release]. South San Francisco, CA: Napo Pharmaceuticals; April 10, 2008.
⁶Holodniy M, Koch J, Mistal M, Schmidt JM, Khandwala A, Pennington JE, Porter SB.
A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol. November 1999;94(11):3267-3273
⁷Review of existing phase 2 trial data indicates positive effect on pain-discomfort-free days in patients with diarrhea predominant irritable bowel syndrome treated with crofelemer [press release]. South San Francisco, CA: Napo Pharmaceuticals; July 10, 2008.
⁸Guerrant RL, Kosek M, Moore S, Lorntz B, Brantley R, Lima AA. Magnitude and impact of diarrheal diseases. Archives of medical research. July-August 2002;33(4):351-355.
⁹Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science. October 7, 1994;266(5182):107-109.