Merlin Willcox

Traditional herbal medicines for malaria

Traditional medicines have been used to treat malaria for thousands of years and are the source of the two main groups (artemisinin and quinine derivatives) of modern antimalarial drugs. With the problems of increasing levels of drug resistance and difficulties in poor areas of being able to afford and access effective antimalarial drugs, traditional medicines could be an important and sustainable source of treatment. The Research Initiative on Traditional Antimalarial Methods (RITAM) was founded in 1999 with the aim of furthering research on traditional medicines for malaria.1 The initiative now has in excess of 200 members from over 30 countries. It has conducted systematic literature reviews and prepared guidelines aiming to standardise and improve the quality of ethnobotanical, pharmacological, and clinical studies on herbal antimalarials and on plant based methods of insect repellence and vector control. We review some of this work and outline what can be learnt from the developing countries on the management and control of malaria. We carried out searches of relevant articles published up to 2004 through Medline, Embase, CAB, Sociofile, and the central clinical trials database of the Cochrane Library, using the terms “traditional medicine” and “malaria”, “malaria-therapy”, “knowledge,-attitudes,-practice”, “self-medication”, and “drug-utilisation”. We also searched the references of identified articles and handsearched journals on ethnobotany, herbal medicines, and tropical medicine, such as the Journal of Ethnopharmacology, Fitoterapia, Transactions of the Royal Society of Tropical Medicine and Hygiene, Tropical Medicine , and International Health . Authors were contacted for unpublished papers. #### Summary points Over 1200 plant species from 160 families are used to treat malaria and fever On average, a fifth of patients use traditional herbal remedies for malaria in endemic countries Larger, more rigorous randomised controlled trials are needed with long term follow up So far only a few studies have reported on side effects from …

Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions

BackgroundIn traditional medicine whole plants or mixtures of plants are used rather than isolated compounds. There is evidence that crude plant extracts often have greater in vitro or/and in vivo antiplasmodial activity than isolated constituents at an equivalent dose. The aim of this paper is to review positive interactions between components of whole plant extracts, which may explain this.MethodsNarrative review.ResultsThere is evidence for several different types of positive interactions between different components of medicinal plants used in the treatment of malaria. Pharmacodynamic synergy has been demonstrated between the Cinchona alkaloids and between various plant extracts traditionally combined. Pharmacokinetic interactions occur, for example between constituents of Artemisia annua tea so that its artemisinin is more rapidly absorbed than the pure drug. Some plant extracts may have an immunomodulatory effect as well as a direct antiplasmodial effect. Several extracts contain multidrug resistance inhibitors, although none of these has been tested clinically in malaria. Some plant constituents are added mainly to attenuate the side-effects of others, for example ginger to prevent nausea.ConclusionsMore clinical research is needed on all types of interaction between plant constituents. This could include clinical trials of combinations of pure compounds (such as artemisinin + curcumin + piperine) and of combinations of herbal remedies (such as Artemisia annua leaves + Curcuma longa root + Piper nigum seeds). The former may enhance the activity of existing pharmaceutical preparations, and the latter may improve the effectiveness of existing herbal remedies for use in remote areas where modern drugs are unavailable.

A “reverse pharmacology” approach for developing an anti-malarial phytomedicine

A “reverse pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “reverse pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.

Do ethnobotanical and laboratory data predict clinical safety and efficacy of anti-malarial plants?

BackgroundOver 1200 plant species are reported in ethnobotanical studies for the treatment of malaria and fevers, so it is important to prioritize plants for further development of anti-malarials.MethodsThe “RITAM score” was designed to combine information from systematic literature searches of published ethnobotanical studies and laboratory pharmacological studies of efficacy and safety, in order to prioritize plants for further research. It was evaluated by correlating it with the results of clinical trials.Results and discussionThe laboratory efficacy score correlated with clinical parasite clearance (rs=0.7). The ethnobotanical component correlated weakly with clinical symptom clearance but not with parasite clearance. The safety component was difficult to validate as all plants entering clinical trials were generally considered safe, so there was no clinical data on toxic plants.ConclusionThe RITAM score (especially the efficacy and safety components) can be used as part of the selection process for prioritising plants for further research as anti-malarial drug candidates. The validation in this study was limited by the very small number of available clinical studies, and the heterogeneity of patients included.

Argemone mexicana decoction versus artesunate-amodiaquine for the management of malaria in Mali: Policy and public-health implications

A classic way of delaying drug resistance is to use an alternative when possible. We tested the malaria treatment Argemone mexicana decoction (AM), a validated self-prepared traditional medicine made with one widely available plant and safe across wide dose variations. In an attempt to reflect the real situation in the home-based management of malaria in a remote Malian village, 301 patients with presumed uncomplicated malaria (median age 5 years) were randomly assigned to receive AM or artesunate-amodiaquine [artemisinin combination therapy (ACT)] as first-line treatment. Both treatments were well tolerated. Over 28 days, second-line treatment was not required for 89% (95% CI 84.1-93.2) of patients on AM, versus 95% (95% CI 88.8-98.3) on ACT. Deterioration to severe malaria was 1.9% in both groups in children aged </=5 years (there were no cases in patients aged >5 years) and 0% had coma/convulsions. AM, now government-approved in Mali, could be tested as a first-line complement to standard modern drugs in high-transmission areas, in order to reduce the drug pressure for development of resistance to ACT, in the management of malaria. In view of the low rate of severe malaria and good tolerability, AM may also constitute a first-aid treatment when access to other antimalarials is delayed.

A clinical trial of the traditional medicine Vernonia amygdalina in the treatment of uncomplicated malaria.

BACKGROUND The leaves of the shrub Vernonia amygdalina Del (Compositae) are widely used in Africa to treat malaria. It is widely available, accessible, and affordable in many remote areas that do not have ready access to modern medicines. INTERVENTION This study examined the efficacy and safety of an infusion of fresh V. amygdalina leaves for the treatment of uncomplicated malaria in patients aged 12 years and over. OUTCOME MEASURES The primary outcome measure was an adequate clinical response. The secondary outcome measure was incidence of adverse events, assumed to be side-effects of the medicine. RESULTS The remedy was associated with an adequate clinical response (ACR) at day 14 in 67% of cases. However, complete parasite clearance occurred in only 32% of those with ACR, and of these, recrudescence occurred in 71%. There was no evidence of significant side-effects or toxicity from the medication. There was a trend toward a reduction in hemoglobin between day 0 and day 28, although this did not reach statistical significance. CONCLUSIONS Further studies are needed to determine whether the efficacy can be improved by increasing the dose, changing the preparation, or adding other antimalarial plants.

Evaluation and pharmacovigilance of projects promoting cultivation and local use of Artemisia annua for malaria

BackgroundSeveral non-governmental organisations (NGOs) are promoting the use of Artemisia annua teas as a home-based treatment for malaria in situations where conventional treatments are not available. There has been controversy about the effectiveness and safety of this approach, but no pharmacovigilance studies or evaluations have been published to date.MethodA questionnaire about the cultivation of A. annua, treatment of patients, and side-effects observed, was sent to partners of the NGO Anamed in Kenya and Uganda. Some of the respondents were then selected purposively for more in-depth semi-structured interviews.ResultsEighteen partners in Kenya and 21 in Uganda responded. 49% reported difficulties in growing the plant, mainly due to drought. Overall about 3,000 cases of presumed malaria had been treated with A. annua teas in the previous year, of which about 250 were in children and 54 were in women in the first trimester of pregnancy. The commonest problem observed in children was poor compliance due to the bitter taste, which was improved by the addition of sugar or honey. Two miscarriages were reported in pregnant patients. Only four respondents reported side-effects in other patients, the commonest of which was vomiting. 51% of respondents had started using A. annua tea to treat illnesses other than malaria.ConclusionsLocal cultivation and preparation of A. annua are feasible where growing conditions are appropriate. Few adverse events were reported even in children and pregnant women. Where ACT is in short supply, it would make sense to save it for young children, while using A. annua infusions to treat older patients who are at lower risk. An ongoing pharmacovigilance system is needed to facilitate reporting of any adverse events.

Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'?

Objectives  Hypoglycaemia (glucose <2.2 mmol/l) is a defining feature of severe malaria, but the significance of other levels of blood glucose has not previously been studied in children with severe malaria.

Ethnobotanical study of plants used against malaria in Sélingué subdistrict, Mali

ETHNOPHARMACOLOGICAL RELEVANCE Plants have contributed to food security and disease treatments to rural populations in sub Saharan Africa for many centuries. These plants occupy a significant place in the treatment of diseases, such as malaria. In Mali, malaria is the leading cause of medical consultation and death. This infection is particularly dangerous for pregnant women and children under 5 years. The general aim of this research was to collect data on the knowledge of traditional health practitioners on malaria in the Sélingué area; particularly to document how traditional healers conceptualize and diagnose malarial disease and to collect and identify medicinal plants or other substances used for their health and well-being. MATERIALS AND METHODS An ethnobotanical survey was conducted on simple and complicated malaria in six villages in Sélingué subdistrict in a period of 2 months. The ethnobotanical data was collected by means of semi-structured interviews and questionnaires. In total 50 traditional healers were interviewed. RESULTS Two concepts of malaria (simple and complicated malaria) were cited and 97 plants used to treat malaria were identified. Decoctions and bathing (whole body) proved to be the most commonly used mode of application. Food attitudes and mosquitoes are perceived to be the most important causes of the disease. Trichilia emetica, Mitragyna inermis, Sarcocephalus latifolius, Cassia sieberiana, Cochlospermum tinctorium, Anogeissus leiocarpa, Guiera senegalensis and Entada africana were quoted as the most used in the treatment of malaria. CONCLUSION Knowledge about malaria and traditional treatment practices exist in Sélingué subdistrict. Herbal remedies are commonly used by people for the treatment of malaria because they are believed to be cost-effective and more accessible. Many of the plant species used for the treatment of malaria have not been well documented as well as their phytochemical and antimalarial activity.

Why there is an inverse primary-care law in Africa

www.thelancet.com/lancetgh Vol 1 December 2013 e332 universal health coverage—a goodquality clinical workforce is needed that has access to diagnostic and treatment facilities, and is incentivised to work where it is most needed. In low-income and middle-income countries, this need is invariably greatest in primary care and fi rst-contact care, both because of the nature of the health services that most need to be delivered, and the importance of primary care for health-system cost-eff ectiveness. The inescapable and unrecognised implication of what our respondents said is that, in most of sub-Saharan Africa, effective primary care is not going to happen. Clinicians will not work in the conditions they experience in primary care, and these conditions are getting progressively worse as the need for effective primary care increases—thus the situation could be called the inverse primary care law. The policy discourse on universal health care in Africa now needs to focus on how to provide the necessary human resources to staff and deliver primary care eff ectively. Demand-led payment systems, such as payment by results, cannot drive up care quality unless there is a supply of well trained and well supported clinical staff to meet the demand. Innovative supply-side solutions could address poor working environments and career paths in primary care. Until these solutions are prioritised and implemented, the global poor are condemned to receive poor care or no care at all.