Diarrhea is generally described according to several criteria: duration (acute vs. chronic), clinical description (frequency, water content, presence of blood), and etiology. Chronic diarrhea has been described as two to three or more loose or watery stools per day for a period of at least 30 days.
It is important to distinguish chronic diarrhea from acute diarrhea. Chronic diarrhea is a distinct clinical entity from acute diarrhea that, if unchecked, results in morphological and functional pathology in the intestine. As opposed to acute diarrhea, histological examination of the chronically infected small intestinal mucosa reveals villus atrophy, crypt hypertrophy, and decreased mitosis. Chronic diarrhea leads to malabsorption, weight loss and cachexia. Both the World Health Organization (WHO) and the Center for Disease Control (CDC) have recognized this condition as the "Diarrhea Wasting Syndrome".
It is often possible to trace the cause of the clinical symptoms of chronic diarrhea in immunosuppressed patients to one or more organisms found in the intestinal tract. In these immunosuppressed individuals, microbes which are relatively harmless to the normal individual take advantage of the very weak immune response to establish a persistent opportunistic infective state. For example, in immunosuppressed patients, such as those with Acquired Immunodeficiency Syndrome (AIDS), chronic diarrhea has been ascribed to the presence of the HIV virus itself, to cytomegalovirus, to the presence of various toxic bacteria, and frequently to infection by pathogenic protozoa. Prevalent among the pathogenic protozoa associated with the presence of diarrhea in immunosuppressed patients are intracellular microsporidia and cryptosporidia (Goodgame, R. W. Ann. Int. Med. 124:429-441 (1996)). In healthy individuals, microsporidial and cryptosporidial infections are self-limiting but immunosuppressed patients can not mount an effective enough immune response to eliminate the causative organism.
Successful clinical management of chronic diarrhea in immunosuppressed patients requires control of the symptoms as well as elimination of the causal pathogen. The lack of effective treatment for the symptoms and causes of chronic diarrhea is a long recognized problem for which no completely satisfactory answer exists. Therapies which may be sufficient to treat acute diarrhea may be ineffective in the treatment of chronic diarrhea. Any benefit from these therapies may be short-lived or may produce adverse side effects with chronic administration. Currently there are no completely effective therapies for immunosuppressed patients with chronic diarrhea, particularly those associated. with microsporidiosis or cryptosporidiosis.
This lack of effective therapy is particularly important in the case of cryptosporidiosis as the diarrhea is usually quite severe and often requires hospitalization and rehydration therapy to overcome dehydration and electrolyte imbalance. Cryptosporidiosis caused by Cryptosporidium parvum has been treated with the aminoglycoside antibiotic, paromomycin. However relapse after cessation of treatment is common. The somatostatin analog, octreotide (Wittner et al., Parasitic Diseases, vol. 7(3): 569-586 (1993)), has been reported to control the voluminous gastrointestinal secretion caused by cryptosporidia in AIDS patients, but diarrhea promptly returns following cessation of treatment.
Albendazole has been reported to temporarily relieve the diarrhea of some AIDS patients infected with microsporidia. Blanshard et al. (AIDS, vol. 6:311-313 (1992)) reported that albendazole was effective in resolving the chronic diarrhea of six AIDS patients with microsporidiosis caused by Enterocytozoon bieneusi. Albendazole appeared to cause degenerative changes in the parasite, but no significant reduction in parasite load was observed after oral treatment. Four of five patients relapsed within one month, and the fifth patient relapsed within two months. Blanshard et al. (J. Clin. Pathol. 46:898-902 (1993)) described the remission of diarrhea in 70% of 18 AIDS patients treated for microsporidiosis with albendazole, this time accompanied by a reduction in parasite load in those patients who responded. Albendazole was reported to slow the rate of parasite reproduction by interfering with tubulin polymerization. The drug did not completely arrest development, however, and the authors speculated that some strains might be partially resistant. Dieterich et al. (J. Infectious Diseases, vol. 169:178-183 (1994)) confirmed that albendazole improved symptoms and reduced the parasite burden in some of their 29 patients infected with E. bieneusi. However, following treatment, small bowel biopsies revealed that E. bieneusi spores were still present.
Another microsporidial species, Encephalitozoon intestinalis (formerly Septata intestinalis), infects macrophages as well as enterocytes and therefore can disseminate to different organs. Molina et al. (J. Infectious Diseases, 171:245-249 (1995)) reported that, although albendazole was initially effective in clearing E. intestinalis from the stools of the five AIDS patients they studied, relief was only temporary. Spores of E. intestinalis were again detected in stools from two of four patients followed for more than one month. Relapse occurred in one patient while receiving maintenance therapy with albendazole.
Berberine (5,6-Dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium) is an alkaloid present in various species of Berberis and several other plant families. Oral berberine has both antisecretory and antimicrobial properties and is nontoxic at high doses.
For many centuries, berberine extract from plants has been used by traditional practitioners in both India and China to manage a variety of medical conditions, including acute diarrhea. In the laboratory, berberine shows in vitro activity against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, several of the protozoal strains which cause leishmaniasis, as well as several types of fungi and bacteria. In the clinical setting, berberine, purified as a hydrochloride, sulfate, or tannate salt, has been used to treat bacterial, fungal and some protozoal infections. Orally administered berberine has been shown to be a safe and effective agent against acute diarrhea, such as that caused by the protozoal pathogen G. lamblia. Healing of sores caused by cutaneous species of leishmanial parasites has been effected by intradermal administration of berberine. Berberine has also proven useful in the treatment of acute diarrhea induced by Escherichia coli and Vibrio cholerae toxins.
Other uses of various berberine are disclosed in Maroko, U.S. Pat. Nos. 5,153,178, 4,980,344, 4,749,708, and 4,761,417, each of which is incorporated herein by reference.