Great Ape Self-Medication and Human Traditional Medicine- A Bio-Cultural Approach to Evaluating Herbal Anthelmintics for Humans and Production Animals in Africa

 

Great Ape Self-Medication and Human Traditional Medicine- A Bio-Cultural Approach to Evaluating Herbal Anthelmintics for Humans and Production Animals in Africa

 

Huffman¹[Huffman1] , M.A., Waller², P.J, Ohigashi¹, H., Yole³, D., Mwenda³, J., Nkunya⁴, M.H.H., Mbago4, F., Elias⁵ R., Gasquet⁵ M., Boegh⁶, H., Kalunde⁷ M.S.,

 

¹ Kyoto University (Japan), ²SWEPAR, National Veterinary Institute (Sweden), ³Institute of Primate Research (Kenya), ⁴University of Dar es Salaam (Tanzania), ⁵Universite de la Mediterranee Aix-Marseille II (France), ⁶Danish Center for Experimental Parasitology (Denmark), ⁷ Tanzania National Parks (Tanzania)

 

 

    Parasite resistance to modern anthelmintics is an increasingly serious problem in human health care and particularly livestock husbandry in Africa and around the world. The study of host-parasite relationships in nature can provide alternatives and important insights into dealing with this problem. Multi-disciplinary investigations of chimpanzee behavioral strategies in the wild and ethnoveterinary / ethnomedicinal surveys of traditional African medicine for the control of parasite infection are being conducted by our multiregional, multidiscplinary research group.  This paper reviews some recent findings and outlines future directions of our research. 

    In wild chimpanzees of western Tanzania and Uganda, ingestion of the medicinal plant Vernonia amygdalina and the non-nutritional use of bristly leaves from other species has been shown to reduce worm burdens of Oesophagostomum and Bertiella spp. providing temporary relief from gastrointestinal upset in this primate species (Huffman et al., 1993; 1996a; Wrangham, 1995). In vitro pharmacological assays demonstrated antischistosomal and antimalarial activities in some of these plant species (Ohigashi et al., 1994). For numerous African ethnic groups, a concoction made from V. amygdalina is prescribed treatment for malarial fever, schistosomiasis, amoebic dysentery, several other intestinal parasites and stomach aches. These striking similarities between the use of this plant species in both chimpanzees and humans suggest strong bio-cultural patterns in the selection and use of some natural medicines (Huffman, Koshimizu, Ohigashi, 1996). Cross-comparison of primate and human medicinal plant use for similar diseases makes use of two highly selective strategies of parasite control for the identification and evaluation of promising anthelmintics.

    A variety of non-nutritional plant secondary compounds are found in the primate diet, but little is known about the possible medicinal consequences of their ingestion. Detailed behavioral, pharmacological and parasitological investigations are currently underway to elucidate the full potential of the primate diet for the prevention and control of illness and in particular parasite infection. The hypothesis currently being developed from our investigations of self-medication in the great apes (chimpanzee, bonobo, lowland gorilla, orangutan) is that such behavior aids in the control of intestinal parasites and provides relief from gastrointestinal upset (Huffman et al., 1996a).

    Parasites are the cause of a variety of diseases that affect the behavior and reproductive fitness of an individual and make the need to counteract such pressure of extreme importance to the host. Such adaptive responses to parasite infection are undoubtedly the products of a long evolutionary process. The amount of detailed information on self-medication gathered thus far is greatest for the African great apes, however, given the obvious adaptive significance that self-medication implies, it is expected to occur in other non-human primates and other animal species as well (Huffman, 1997).

    It has been convincingly argued that the herbal medicines and modern pharmaceuticals used by humans today have replaced the non-nutritive chemicals commonly present in extant primate and early hominid diets. There is a fine line between what may be ‘medicine’ and what is ‘food’ in primates, making the difference often seem transparent. Much of what is consumed daily contains an array of secondary compounds.  J. Berry (Division of Biological Sciences, Cornell University) has found up to 30% of the herbaceous diet of mountain gorillas to possess antibacterial properties. In many traditional human societies as well food and medicine greatly overlap in the diet.  For example, in Japanese the saying ‘ishoku dougen’ means medicine and food are of the same origin.  N. Etkin (University of Hawaii) found that 30% of the plant species identified as foods among the Hausa of Nigeria in Western Africa were also used as medicine.  Likewise, 89% of species used to treat symptoms of malaria were also used in a dietary context (Etkin, 1996; Etkin and Ross, 1983).  From this view point, it is clear that we have much to gain by taking a closer look at the pharmacological characteristics of both the proposed self-medicative and daily dietary items and behavior of animals in the wild.

 

GREAT APE CHEMICAL ECOLOGY

    Chimpanzees, bonobos and lowland gorillas are largely frugivorous but also consume the leaves, pith, seeds, flowers, bark and sap of many species.  A variety of interesting secondary compounds have been isolated from some of these plant parts (Koshimizu et al., 1993; Koshimizu, Ohigashi, Huffman, 1994; Ohigashi et al., 1991). Secondary compounds as well as inorganic materials are a plant’s defense against most herbivorous predators. These products are toxic to the consumer or inhibit consumption by reducing palatability or digestibility, yet a number of items under this category can be found in the great ape diet. Many are also recognized ethnomedicinal plants.

Ethnomedicinal uses of secondary compound rich fruits and leaves

    The secondary compound rich content of nutritious foods in the diet eaten under apparently normal situations may play a significant role in the maintenance of health.  A literature search was made for plant foods reported to be ingested by the Mahale chimpanzees in western Tanzania using references on African ethnomedicine in order to estimate the potential contribution to parasite control by medicinal plants included in the diet.

    From the 192 recognized plant food species, 172 were selected for this analysis on the basis that they are not cultigens and that a positive scientific identification has been made. While it was common for some species to have multiple ethnomedicinal uses, 43 (22%) of these 172 species were reported to be used to treat parasitic or gastrointestinal related illnesses. While not all 43 species may be ingested by chimpanzees in such a way as to benefit from these potential medicinal properties, 33% (20/63) of the plant parts ingested from 16 of these species corresponded to the parts utilized by humans for the treatment of intestinal parasites and gastrointestinal illness (Huffman et al., 1998).

    Interestingly, for those 16 species there is a significant trend for them to be ingested more frequently during the rainy season months, as are the medicinally used species described below which are proposed to be used solely for the control of nodular worm infections (Huffman et al., 1996b).

 

SELF-MEDICATIVE BEHAVIORS OF THE AFRICAN GREAT APES

    Among chimpanzees, gorillas and bonobos, two proposed types of self-medicative behavior, bitter pith chewing and leaf swallowing, have been documented to date.

The behavioral ecology of bitter pith chewing

    Bitter pith chewing aids in the control of intestinal nematode infection and relief from gastrointestinal upset via pharmacological action. The hypothesis that bitter pith chewing has medicinal value for chimpanzees was first proposed from detailed behavioral observations and later from parasitological and phytochemical analyses of patently ill chimpanzees ingesting Vernonia amygdalina Del. (Asteraceae) at Mahale by Huffman and Mohamedi Seifu Kalunde (Huffman and Seifu, 1989).

    When ingesting the pith of young shoots of V. amygdalina, Mahale chimpanzees first remove the outer bark and leaves to chew only on the exposed inner part, from which they extract the bitter juice. The amount of pith ingested for a single dose is relatively small, ranging from portions of 5 to 120 cm in length X 1 cm in diameter. The entire process, depending on the amount ingested takes anywhere from less that one to 8 minutes. 

    Regardless of year-round availability, use by chimpanzees is rare and highly seasonal. Bitter pith chewing occurs mainly just after the onset of the rainy season.  A three year longitudinal study of the individual parasite infection levels of Mahale chimpanzees has demonstrated a significant rainy season increase in the incidence of infections for individuals infected by Oesophagostomum stephanostomum (nodule worm), but not for other nematode species.  Nodular worm infections were associated significantly more frequently with bitter pith chewing and leaf swallowing, than either Strongyloides fullebornii (whip worms) or Trichuris trichiura (thread worms).

    Detailed observations of bitter pith chewers demonstrate ill health (diarrhea, malaise and nematode infection) at the time of use. In two closely monitored cases of bitter pith chewing in sick individuals, recovery was noted within 20-24 hr. In one case the eggs per gram feces (EPG) level of a nodular worm infection was found to have dropped from a count of 130 to 15 within 20 hours. No change occurred in this individual’s concurrent whip worm infection. In most individuals monitored at the same time, nodular worm EPG levels increased over time (Huffman and Seifu, 1989; Huffman et al., 1993). The recognized increases in EPG levels represent the overall trend for increased reinfection by nodular worms at the beginning of the rainy season. It is at this time that individuals begin to reduce the number of worms parasitizing them.

The behavioral ecology of leaf swallowing

     Leaf swallowing also aids in the control of nodule worm infections and is believed to relieve pain caused by tapeworm infection via the expulsion of these intestinal parasites. Both phytochemical and physical mechanisms for parasite removal have been proposed.

    Leaf swallowing behavior was first recorded for chimpanzees at Gombe and Mahale. As of January 1, 2000, leaf swallowing behavior involving 34 different plant species has been noted to occur in 9 populations of chimpanzees, 3 of bonobos and one of eastern lowland gorillas at 13 sites across Africa. The common property linking all of these plants is their bristly, rough-surfaced leaves (Huffman, 1997). The hairs or trichomes on the leaf surface vary from long and slender, thorn like, hooked to sharply spiked.

    The distal half of these leaves are selected one at a time, folded by tongue, lips and palate as they are slowly pulled into the mouth and then individually swallowed whole. An individual may swallow anywhere from one to 55 leaves in a single bout, repeatedly over a day. Like bitter pith chewing, leaf swallowing is an extremely rare behavior. Although the leaves of all species selected are available year-round, like bitter pith chewing at Mahale, use is most common after the beginning of the rainy season.

    Behavioral and health profiles collected concurrently with direct observations of leaf swallowing reveal signs of diarrhea, malaise and suggestion of abdominal pain. Nematode infection has been demonstrated in 83% of all leaf swallowing cases observed directly or documented indirectly from dung containing leaves. The occurrence of adult worms in the dung is rare (3% 9/254) and has thus far been limited to leaf swallowing.  All such worms recovered have been identified as nodular worms of the species O. stephanostomum.

    A strong relationship is recognized between leaf swallowing and the expulsion of these nodular worms.  The relationship is statistically highly significant. Leaves are typically swallowed first thing in the morning on an empty stomach. This is observed to result in at least a 17.4 h reduction in transit time. The leaves have been measured to pass through the GI tract as quickly as 6 hours.  All worms recovered are alive and motile at the time of inspection eliminating the possibility of a chemically induced nematocidal property in the leaves.  Instead, the purging of worms largely via the leaves’ physical properties is hypothesized to be the main mechanism of leaf swallowing (Huffman and Caton, in press).

    Similar reports exist for the expulsion of Ascaris by a leaf swallowing domestic dog in Tanzania, of tapeworms by brown bears in Alaska and similarly by snow geese in Canada (Huffman, 1997; Huffman and Caton, in press).

 

PHARMACOGNOSY AND ETHNOPHARMACOLOGY OF CHIMPANZEE SELF-MEDICATIVE BEHAVIORS

Bitter pith chewing

    Among numerous African ethnic groups, a concoction made from V. amygdalina is used to treat malarial fever, schistosomiasis, amoebic dysentery, several other intestinal parasites and stomachaches. The noted recovery time of 20-24 hours after bitter-pith chewing in two M group chimpanzees is comparable to that of local human inhabitants, the Tongwe, who use cold concoctions of this plant as a treatment for parasite infection, diarrhea and stomach upset (Huffman et al., 1993).

    Some of the other species with bitter piths ingested by chimpanzees elsewhere have a number of ethnomedicinal and pharmacological properties worth mentioning. V. colorata and V. amygdalina, very closely related species, are not distinguished from each other by traditional African healers with regard to their medicinal properties and folk classification (Dalziel, 1937).  Alkaloids found in the pith, as well as flower and leaf of V. hochstetteri may possess some sort of biological activity. P. hirsuta and E. macrocarpa are used in west African ethnomedicine for the treatment of upset stomachs, colic, as an antiseptic and analgesic and for venereal disease.  Molluscicidal activity has also been reported for P. hirsuta (Abbiw, 1990; Okunji and Iwu, 1988).

    Phytochemical analysis of V. amygdalina samples collected at Mahale from plants known to be used by chimpanzees reveal the presence of two major classes of bioactive compounds. To date, a total of 4 known sesquiterpene lactones, 7 new stigmastane-type steroid glucosides and 2 freely occurring aglycones of these glucosides have been isolated (Jisaka et al., 1992 a; 1993).

  Supportive of the ethnomedicinal literature, the sesquiterpene lactones present in V. amygdalina, V. colorata and a number of other Vernonia spp., are well known for their anthelmintic, antiamoebic, antitumor, and antibiotic properties (e.g. Burkill, 1985; Dalziel, 1937; Watt and Breyer-Brandwijk, 1962). From crude methanol extracts of the leaves, we also found inhibition of tumor promotion and immunosupressive activities (Jisaka et al., 1992 a, b).

    In vitro tests on the antischistosomal activity of the pith's most abundant steroid glucoside (vernonioside B1) and sesquiterpene lactone (vernodaline) showed significant inhibition of movement of the adult parasites and adult females’ egg-laying capacity (Jisaka et al., 1992 b).  These findings are consistent with the observed decline in nodular worm EPG level 20 hours after an adult female chimpanzee at Mahale ingested V. amygdalina pith (Huffman et al., 1993). 

    While abundant in the leaves and bark, the highly toxic vernodaline occurs in only insignificant amounts in the pith. This may explain why chimpanzees normally avoid ingesting leaves and bark in preference for the pith, with its greater abundance of steroid glucosides and their aglycones (Ohigashi et al., 1994). 

    In vitro tests on the antiparasitic activity of both the sesquiterpene lactones and the steroid glucosides, using Leishmania infantum, Entamoeba histolytica, and a K1 multi-drug resistant strain of Plasmodium falciparum have also been conducted.  The sesquiterpene lactones showed significant plasmodicidal activity although the IC₅₀ values were more than 20 times higher than that of the common commercial agent, chloroquine diphosphate. The steroid glucosides showed weaker plasmodicidal activity. However, as in the case described above, the activity of their aglycones was significantly higher in both plasmodicidal and amoebicidal testing. In particular, a significant increase in the plasmodicidal activity of vernoniol A4 was noted (Ohigashi et al., 1994).

Leaf swallowing

    Behavioral, parasitological and physiological observations pertaining to leaf swallowing have been integrated to elucidate the mechanism likely responsible for the expulsion and control of nodule worm infections by the ape host.  Physical irritation produced by bristly leaves swallowed on an empty stomach, were associated with an increase in motility and secretion resulting in diarrhea which rapidly moved the swallowed leaves through the GI tract in about 6 hours, or about 17 hours faster than normal.  In the proximal hindgut, the site of L3 (third stage larvae) cyst formation and adult worm attachment, motility, secretion and the scouring effect of rough leaves is proposed to be greatly enhanced by haustral contractions and peristalsis- antiparistaltis.  Frequently, at the peak of reinfection, a proportion of non-encysted L3 (stage of parasite that is ingested by the host leading to infection) is predictably vulnerable to this.  These factors are proposed to result in the disruption of the life cycle of Oesophagostomum spp.  Repeated flushing during peak periods of reinfection is believed responsible for the observed long-run reduction of worm burdens at certain times of the year (Huffman et al., 1997).  In this light, leaf-swallowing can be viewed as a deliberate adaptive behavioral strategy with physiological consequences for the host.  The expulsion of worms based on the activation of basic physiological responses in the host is a novel hitherto undescribed form of parasite control (Huffman and Caton, in press).

 

NEW STRATEGIES FOR THE TREATMENT OF PARASITE DISEASE AND ANTHELMINTIC RESISTANCE?

    Some nodular worm species are a significant pathogen in domestic livestock, non-human primate and occasionally human hosts.  Symptoms of moderate to heavy infections of O. stephanostomum, O. bifurcum and O. aculeatum reportedly range from weight loss, enteritis, diarrhea, anemia and lethargy to anorexia and intense pain simulating appendicitis.  Pathology includes hemorrhagic cysts containing larvae, septicimia resultant from bacterial invasion of lesions in the colon, blockage of the colon due to gross thickening of the wall, epigastric or periumbilical masses clearly visible from the outside.  Gross lesions in submucosal or suberserosal nodules (5 - 20 mm diameter) are associated with the larvae.  These cysts or nodules contain caseous, necrotic centers in a fibrous capsule.  Histology includes intense inflamatory cell reaction accompanied by high levels of neutrophils and eosinophils associated with the nodules (above reviewed from Polderman and Blotkamp, 1995). Control of such infections by the host is of obvious adaptive significance.

    Anthelmintic resistance is a serious problem for livestock management and resistance to drugs used in treating life threatening diseases such as schistosomiasis and malaria in humans is a global problem urgently in need of solutions (Geerts and Dorny, 1995; Jackson, 1993). The widespread geographical occurrence and broad taxonomical representation of great ape species exhibiting leaf swallowing and bitter pith chewing behaviors suggests that these self-medicative behaviors represent a stable biological strategy for parasite control. Can the study of self-medication in the great apes and other animals offer new ways of countering chemoresistance?

    According to S. Geerts and colleagues factors selecting for anthelmintic resistance are mass treatment, frequent use of the same class of drugs over long periods of time and under dosing (Geerts and Dorny, 1995).  Theoretically therefor the converse approach may help stem anthelmintic resistance.  Indeed, it has been recommended that:

I. minimizing treatments,

II. rotating or combining different chemotherapies, and

III. proper dosage

be practiced to stem or control anthelmintic resistance in livestock and human treatment programs (Geerts, Coles and Gryseels, 1997; Kremsner et al., 1997). The observations of chimpanzee self-medication support these recommendations and suggest that further detailed behavioral and chemo-ecological studies of great ape behavior may provide significant insight into more natural systems of parasite control which inhibit the development of parasite chemoresistance and effectively maintain the health of animals under human care.

    A number of ethnomedicinally recognized plants used for the treatment of intestinal parasite infections and related illness were found in the diet of great apes (Huffman et al., 1998).  A preliminary look at both the real and potential pharmacological activity of plants used and the ways they are ingested suggests that the Mahale chimpanzees’ self-medicative and dietary behavior mirrors recommendations I and II above. The ‘control of nematode infection hypothesis’ predicts that since nodular worm infections are typically self-limiting, the total infection may be controllable if a chimpanzee responds to these symptoms during the most likely period of reinfection. At Mahale, the peak period of reinfection by the nodular worm O. stephanostomum was largely limited in time to the one or two months after the onset of the rainy season. The occurrence of bitter pith chewing and leaf swallowing at Mahale peaks during these first few months of the rainy season and supports the principle of minimizing treatment to periods of peak infection. That is, chimpanzees are likely responding only to the discomfort of higher level infections, thus maintaining them as best as possible at manageable sub-clinical levels most of the year.

    Bitter pith chewing and leaf swallowing compliment each other in proposed function but appear to differ greatly in their mode of action. As noted above, the pith of V. amygdalina contains constituents from at least two distinct classes of bioactive compounds, the sesquiterpene lactones and the steriod glucosides. Both bitter pith chewing and leaf swallowing are sometimes displayed by the same individual on the same day. With the apparent bimodal action of these two different behaviors together they may act more effectively towards the control of nodular worm infections. This trend parallels the principle of combining treatments and employing complex chemotherapy.  As this study suggests, this may be even further enhanced by the contribution of a secondary compound rich diet.

 

FUTURE DIRECTIONS AND GOALS

      As the forgoing discussions have suggested, the study of the pharmacognosy of great ape diet, self-medicative behaviors and their corrrelations with documented ethnomedicinal practices promise to provide important leads to future sources of natural medicine for the treatment of parasitosis. In addition to this, a closer look into the manner in which great apes use these natural products or combine them with antiparasitic behavior may provide novel insights into viable strategies for suppressing or slowing down the rate of acquisition of chemoresistance by these parasites.

      The next step is to conduct in vivo tests to determine direct anthelmintic efficacy in a wide range of parasites, using a number of different host species.  Preliminary studies using the pig as a model for monogastric animals (including man) have been conducted on preparations of V. amygdalina at the Center for Experimental Parasitology, Denmark.  Preliminary results were inconclusive but future tests using this and other plant species are in the planning stages.  The freshness of samples, the way they are preserved and transported as well as the location of collection may have important effects on material used.  These and other factors will be further investigated. 

      Differences in metabolism, drug pharmacokinetics etc. between monogastric and ruminant livestock necessitates further screening activities in the latter class of animals.   Protocols for testing herbal preparations against nematode parasites of ruminants, using sheep as the model system, are underway in the Department of Parasitology, National Veterinary Institute, Sweden and the International Livestock Research Institute, Kenya. We are also currently planning for the initiation of in vitro / in vivo model testing of plant extract and raw plant material as foliage on schistosomiasis in baboons and leishmaniasis in vervet monkeys.at the Institute of Primate Research, National Museums of Kenya, Karen Nairobi.

      Basic broad spectrum biological assays of insecticidal and plasmodicidal activity of promising plants and the elucidation of their chemical constitutents are undereway in the Laboratoire de Pharmacognosie - Homeopathie, Parasitologie Universite de la Mediterranee (Aix-Marseile II), France and the Department of Chemistry University of Dar es Salaam, Tanzania.  Technical support on parasite and plant identification is provided by the Departments of Zoology and Botany-Herbarium at the University of Dar es Salaam, Tanzania.  Collaborative support from interested institutions and individuals in other areas of Africa are always welcome. 

      This truly multidisciplinary approach to research, where biological activity of novel, plant derived compounds is being assessed against a whole range of parasite species found across a wide range of hosts, maximises the chance of success. At the same time the research consortium recognizes the importance of preserving the intellectual property rights of the regions/countries to any new discoveries derived from indigenous plant material.  A prime objective of this research is to integrate our results into local health care and livestock management systems so that locally available plants can be properly used to the benefit of all.

 

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 [Huffman1]