Gaia Research - Traditional African Medicine

Alpa Popat ^a,b, Neil H. Shear ^a,b, Izabella Malkiewicz ^a, Michael J. Stewart ^c, Vanessa Steenkamp ^c, Stuart Thomson ^d and Manuela G. Neuman ^a,b ^*

^a Division of Clinical Pharmacology, E240, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada
^b Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
^c Toxicology Unit, Department of Chemical Pathology, South African Institute for Medical Research, University of the Witwatersrand, Witwatersrand, South Africa
^d Gaia Research Institute, Knysna, South Africa

Received 8 February 2001; received in revised from 21 March 2001; accepted 27 March 2001

Objectives: To review the literature on the toxicity of Callilepis laureola, and to assess the cytotoxicity of C. laureola in human hepatoblastoma Hep G2 cells in vitro.

Design and methods: Cells were incubated for up to 48 h in the presence of increasing concentrations of an aqueous extract of C. laureola (0.3-13.3 mg/mL). Cytotoxicity was quantitated spectrophotometrically by the metabolism of the tetrazolium dye MTT. Cytoviability of the control cells was considered to be 100%.

Results: C. laureola produced cytotoxicity in a concentration-dependent manner. Cytotoxicity was significant at all concentrations tested (0.3-2.5 mg/mL, p < 0.05 vs. controls and 3.3-13.3 mg/mL, p < 0.0001 vs. controls). After 6 h, 100% toxicity was observed at a concentration of 6.7 mg/mL.

Conclusion: C. laureola causes significant cytotoxicity in Hep G2 cells in vitro. These findings are in accordance with the observed hepatotoxicity in clinical cases of C. laureola poisoning.

Keywords: Callilepis laureola; Impila; African; Traditional herbal medicines; Hep G2 cells; Hepatotoxicity

Introduction

There is a mythical yet predominant view that herbal medicines are harmless and free of side effects because they are “natural”. There have been several cases, however, of hepatic injury and even death associated with their use. The effective and safe use of medicinal herbs has therefore been identified as a top research priority; and the implementation of regulatory procedures and investigations on safety are currently underway in developed countries.

While not addressed as frequently in the literature, the safety of herbal medicines used in underdeveloped countries is also a major concern. In South Africa, it is estimated that between 60 – 85% of the native population use traditional medicines, usually in combinations. Cases of acute poisoning due to traditional medicines are not uncommon, many of which have resulted in significant morbidity and mortality (18) , with mortality estimated to be as high as 10,000-20,000 per annum (19).

Venter and Joubert analyzed cases of acute poisoning admitted to Ga-Rankuwa Hospital, Pretoria over a 5 year period (1981-1985). Overall, poisoning with traditional medicines resulted in the highest mortality, accounting for 51.7% of all deaths that were due to acute poisoning. Patients were predominantly male and the majority of admissions were children between the age of 1-5 years. Traditional healers were the main source of the medicines, and in some cases substances were bought at a shop for African remedies (21) . The majority of poisonings were accidental, only 4% were due to deliberate self-poisoning. A study by Stewart et al. analyzed the Johannesburg forensic database over 5 years (1991-1995) and found that (African) traditional remedies were involved in 43% of poisoning cases (22) .

While these studies have provided estimates, it is suspected that the true number of poisoning cases from traditional medicines is far greater (23) . Medically certified information on the mortality among native South Africans is lacking, especially for rural areas where deaths are not always registered (19, 23) . Many poisoning cases are thought to remain undiagnosed since patients residing in rural areas may die before reaching a hospital (23) . Furthermore, autopsies are not routinely conducted, and the cause of death is not always determined or documented on the certificate, thus many poisoning cases may go unrecognized.

Detection of traditional medicine poisoning is further complicated due to the lack of analytical techniques required to make a confident diagnosis. Due to a shortage in resources, diagnostic tools are either limited or have not yet been developed. Moreover, the plant component of the traditional remedy responsible for the observed toxicity may not be known. In some cases, the culprit plant has been identified through direct questioning. People are generally very reluctant to admit the use of herbal remedies, however, often because hospitals tend to hold a negative view toward traditional medicines, and also because of the cultural secrecy surrounding their use.

In the present study, we investigate the in vitro hepatotoxicity of one known toxic herb: Callilepis laureola. C .laureola is a traditional remedy commonly used by the Zulu who are predominantly located in the KwaZulu-Natal region in the northeast of South Africa. C. laureola, a member of the family Compositae, is a herbaceous perennial plant found commonly in grassland habitats of eastern South Africa. C. laureola is known to be “very poisonous and has even been responsible for several deaths among the Zulu”. It has been estimated that the plant is responsible for up to 1500 deaths per annum in KwaZulu-Natal alone, one of nine provinces in South Africa (27, 32) . The plant is commonly known as Impila, which ironically is the Zulu word for “health”.

Although there are no approved medical uses of Impila from a health regulatory standpoint, the plant is widely used among the Zulu and appears to serve as a multi-purpose remedy (22) . Reports indicate it is used to treat stomach problems, tape worm infestations, impotence, cough, and to induce fertility. Impila is also administered to pregnant women by traditional birth attendants to “ensure the health of the mother and child” and to facilitate labour. A tonic made from the root is also taken by young girls in the early stages of menstruation. The greatest and most valued attribute of this plant, however, appears to lie in its “protective powers” in warding off “evil spirits”. For example parents who have lost previous children to illness may administer Impila enemas to their current children for the belief it will “protect” them. It is suspected that these magical beliefs are the primary reason for the common use of Impila in young children, and the high Impila-related mortality in children under the age of 5 years (22) .

Impila is most often prepared using the tuberous rootstock of the plant, while the leaves are reputed to have minimal curative properties. The tuber may be harvested and collected in the winter, and dried and crushed into a powder. Alternatively, a fresh piece of the tuber, the size of a forefinger, may be chopped and bruised. The resultant powder is boiled for approximately 30 minutes to 1 hour in a suitable volume of water and the decoction is administered either orally or as an enema. It has been estimated that each dose of the herbal remedy is prepared from approximately 10 grams of plant material (32) .

The danger of C. laureola was first documented in 1909. Numerous cases of Impila-induced hepatic and renal toxicity emerged in the medical literature during the 1970s and since this time there have been regular reports of fatal Impila intoxications. The toxicity of Impila appears to be very sudden in onset, and it is suspected that many patients do not reach a hospital before death (22) . The fatalities due to C. laureola toxicity are significant. As reported by various investigators, it is estimated that 63% of patients die within 24 hours, and a further 28% die within 5 days, thus bringing the total mortality to 91% (23).

Despite it’s reputed toxicity, Impila continues to be a very popular and commonly used traditional remedy in South Africa (23) . If the toxicity of C. laureola is so well established, why then is the plant still being used significantly in South Africa? There appears to be several complex answers to this question. Currently there is no legislation controlling traditional medicines in South Africa, and the regulatory standards and public education required to ensure their safe use have yet to be implemented (19) . In rural areas, traditional healers are the primary source for obtaining such medicines, whereas in towns and cities, traditional medicines are readily available in African medicine shops where they are sold over-the-counter.

Another issue to consider is the cultural context in which traditional medicines are used. Impila is most commonly used for the magical properties it is believed to possess. While some illnesses are attributed to natural causes, others are thought to be the result of an “evil spell”, or the consequence one must suffer for violating the ancestral spirits. The respect for traditional healers and the belief in the curative properties of traditional medicines is so deep-rooted, that often a fatality resulting from a toxic herb will wrongfully be blamed on the underlying “illness” for which the herb was taken. Other points of consideration are the factors that affect the toxicity of the herb itself. The toxicity of some plants is known to vary with season.

The lack of safety regulation and the ease at which herbal medicines may be obtained likely increase the occurrence of fatal errors among traditional healers, vendors and the public in regards to the strict “ancient rules” regarding the use of Impila as an herbal remedy: “impila is never given to a child under the age of 10; it is never given by way of an enema; it is never used in arbitrary doses nor in any but the weakest solution; when swallowed, it must never be allowed to be absorbed; in other words, it is used exclusively in the form of treatment known as phalaza (i.e. swallowing a large volume of a weak decoction, followed by immediate inducement of complete or near-complete catharsis). There is little doubt that a lack in knowledge and awareness of these strict rules has contributed to the numerous cases of Impila-induced fatalities.

Although clinical cases of C. laureola-induced toxicity are well documented in the literature, the mechanism by which the plant produces hepatic and renal toxicity is not completely understood. Cases of human poisoning with C. laureola have been researched by various investigators in South Africa and are well documented in the literature. Diagnostic methods to confirm such poisonings are in the process of development (22) . The mechanism by which C. laureola produces hepatotoxicity is still not known, and to date there are no published data available on the plant’s effects in vitro. Therefore, as a starting point, we report preliminary results of the hepatotoxic effects of C. laureola in vitro using the human hepatoblastoma Hep G2 cell line.

Our results suggest that the principle target of C. laureola-induced toxicity is the mitochondria. The mechanism appears to involve a metabolite-induced opening of the mitochondrial permeability transition pore (MPTP), release of cytochrome c, and caspase activation. Whether apoptosis or necrosis is the predominant mode of cell death involved in C. laureola intoxication will have clinically important implications for treatment interventions and the development of antidotes. The in vitro model used in the present study will be a useful tool to study the mechanism of C. laureola-induced hepatocyte death, and further investigations in this direction are currently in progress.

(For the full technical aspects of this paper, see the full text PDF version associated with this introductory extract.)

Response to du Plooy and Jobson: Estimated Mortalities Due To Traditional African Medicines In South Africa

I humbly submit the following for your urgent consideration for publication in the letters pages of Clinical Biochemistry.

The estimate of 10-20,000 deaths p.a. from traditional African medicines (TAM) in South Africa, cited in "Popat A, et al, Clin Biochem, 34, 2001" as "Thomson S, Traditional African Medicine Genocide and Ethnopiracy, Report to the SA Medicines Control Council, Gaia Research Institute, March 13, 2000" has been criticized without substitution by du Plooy and Jobson as conjecture and lacking peer review. Following requests from the Centre for Epidemiological Research and Trauma Research Unit, both at the SA Medical Research Council, a response was prepared for a review of my methodology, presented below in abbreviated and adapted form for consideration by Clinical Biochemistry readers and detractors. In spite of repeated requests for critique or attempted rebuttal, none has been forthcoming in the subsequent 23 months. If space permits, I have critiqued the mentioned du Plooy et al paper, so that readers might witness and understand their apparent desperation and mischievous intent.

Data on mortality in South Africa is inadequate. The absence of a comprehensive national health information system poses problems for analysis. (White Paper on Population Policy, RSA, March 1998) The SA MRC conceded the dilemma a year prior, stating: “Estimating specific causes of death in South Africa is difficult, the last detailed information being almost a decade old, since the law was changed at that time to exclude the necessity of recording the details of the actual cause of death. The data collection system makes no provision for gathering the type of data needed to determine how many deaths might be attributable to traditional medicines. The overall figures must all be considered to be vast underestimates. There are major problems with the data. Not all deaths in rural areas are registered and many are in the ill-defined category where it was not specified on the certificate.” (Pers comm, Dr D Bradshaw, Centre for Epidemiological Research in Southern Africa, MRC, 6 April 1999)

The data used is the only available, namely, "Bradshaw D, Health and Related Indicators, SA Health Review, 1997", and "Recorded Deaths, 1994, CSS Report No. 03-09-01, Central Statistical Services, Pretoria, 1994". Figures used for comparison were those of the Dept of Health (DoH), confirming the validity thereof. My reasoning is elementary, as follows: The crude death rate in South Africa is 8.9 per 1000 (RSA Stats in Brief, Aug 1996), (9.4/1000 according to DoH), so approximately 400,000 of 40 million die each year. In SA 19.56% of all deaths are of unnatural causes (20% DoH), excluding homicide, violence, accidents and self-afflicted. (Bradshaw D, Estimated Cause of Death Profiles SA, Based on 1990 Data, CERSA, MRC, 1991) 20% of 400,000 clearly suggests 80,000 deaths from unknown causes p.a., possibly from TAM.

Amongst black South Africans, poisoning is the second in order of importance in the five main causes of death. (Van Rensburg H & Mans A, Profiles of Disease and Health Care in South Africa, R&H Academica, 1982) The major cause of fatal poisoning pattern reported at Ga-Rankuwa is very similar to Bloemfontein (and Zimbabwe). The major causes of mortality were TAM, responsible for 51.7 % - 62% of deaths. (Joubert P, J Toxicol Clin Toxicol 28(1), 1990) Many cases are undiagnosed, where patients die without reaching hospital and do not often admit to ingestion of a traditional remedy. (Steenkamp V, et al, Hum Exp Toxicol 18(10), 1999)

It is not unrealistic to assume that TAM is responsible for 10-20% of the deaths from unknown causes, ie 8-16,000. Assuming that just 12,000 (3%) of the deaths from natural causes are likely to be incorrectly allocated TAM mortalities, simply because it is not possible to determine the true causes in all cases and because the symptoms and causes from traditional medicines closely mirror the major causes of death among the South African black population (diarrhoea, fetal distress and renal, hepatic, respiratory & cardiac failure), 20-30,000 would be a realistic estimate, yet I settle for a far more conservative (1.5%) estimate of 10-20,000 TAM mortalities p.a..

In concurrence, US computerized data for nosocomial adverse drug reaction mortalities exceed 100,000 annually. (Lazarou B, et al, Incidence of Adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA, 279: 1200-5, 1998) In South Africa, allopathics are in a 20% minority to 80% for traditionals. A simple extrapolation based on the (1990) US population of 260 million compared to SA’s 40 million, suggests 15,000 ADR mortalities for SA. However, the US figures reflect actual captured data, the true figure being estimated to be double that, in real terms. (Holland E & Degruy F, Amer Home Physician, 56(7), 1997) In SA, 15-30,000 likely ADR mortalities are therefore distributed between allopathic and traditional drugs, supporting my original TAM mortality estimate of 10-20,000 as fairly conservative.

The US figures are for scientific medical drug related hospital deaths, yet ADR’s still rank from the 4th to 6th leading cause of death. (Editorial, Bandolier, UK NHS, June, 52-3, 1998); (White T, et al, Pharmacoeconomics, 15(5), 1999) Contrast this with the Third World facilities and drugs that most African patients do not consider capable of addressing the supernatural causes of their illness/misfortune, let alone avail themselves to. Furthermore, the 400,000 traditional healers and vendors serving 80% of the population do not prescribe or supply TAM on any rational basis other than superstition and their ability to engage patients as drugs of ordeal, to appease angry ancestors rather than for any pharmacological action. Given these circumstances, it is unlikely that South Africa would escape this extrapolated ADR mortality burden.

Comments on Du Plooy and Robson's changing pattern in deaths due to traditional medicine poisonings in the last twenty years at Ga-Rankuwa Hospital

In an article cited in a recent letter to the Editor, Clin Biochem, du Plooy and Jobson state: "In this article we place Joubert's figure of 51.7% in the correct perspective and provide details of the extent of mortality due to traditional medicine poisonings in Ga-Rankuwa patients from July 1996 to July 2000", yet curiously, they fail to do so. They further state: "Unfortunately we were unable to obtain the total number of all deaths for the same period (Mar 97-Mar 98)" and that: "Results are expressed as actual numbers and percentages in terms of five categories in table", yet again, curiously they are not, the period is missing from the table. They do throw around a few figures, including some (only some) missing from the table, divided into the total number of patients, but now curiously, inconsistently inflated by those "seen" or admitted, thereby attempting to trivialise the number of deaths from TAM, but during a period for which they conveniently have no total number of deaths. Additionally, unidentified poisonings, which are likely to include many TAMs, are conveniently excluded from analysis without any quantification, further placing their results in question. The du Plooy et al data is incomplete and unsuitable for comparative analysis. It is alarming that this was peer reviewed and yet still published in the SA J Sci.

Finally, a serious error or fraud is committed, whereby they state that: "It is worth noting that paraffin ingestion "remains" the cause of the highest number of deaths from poisoning". Again, curiously the deaths from paraffin are not even shown. Again, utter nonsense. Paraffin is the biggest cause of acute "poisoning", not of deaths, which latter have always been and remains due to TAM. (Venter C, Joubert P, Biomed Environ Sci 1(4) 1988); (Joubert J, J Toxicol, 28(1), 1990); (Ellenhorn's Medical Toxicology, M Ellenhorn, Ed, William & Wilkins, 1997) It is clear to me that du Plooy and Jobson are desperate to prove something in service of a mischievous agenda.

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