This is a first attempt to devise and pilot a scoring system to prioritize anti-malarial herbal remedies for further research, based on existing ethnobotanical data, and laboratory data on efficacy and safety. The overall score for most promising remedies was over 14, showing good results in all domains. However combining the scores can also have disadvantages. Cinchona (which is highly effective, and the source of quinine, which can be toxic ) scored 6.5 overall (ethnobotanical = 3.5; efficacy = 8; safety = -5) which was the same score as the safe but ineffective topical Shea butter (ethnobotanical = 0.5; efficacy = 0; safety = 6) .
The evaluation of the proposed RITAM score is limited by the paucity of good quality published clinical trials of herbal anti-malarials. Despite an exhaustive literature search, clinical trials of only ten remedies were identified, only five of which had used good quality methods for evaluating parasite clearance, and only three of which had recorded ACR as an outcome. Even in some of these the preparation and dose may not have been optimal.
Definition of clinical outcome is of central importance to this evaluation. Prevention of severe malaria is in fact the desired effect, and can be achieved without total parasite clearance [30, 33], but large numbers of patients are needed in order to detect differences in this outcome, so it is not commonly used. ACR was devised as a surrogate measure but its definition is complex, and may be interpreted slightly differently in different studies . Parasite clearance is a simpler outcome which should have the same definition in different studies, but its relevance is debatable in high transmission areas where reinfection occurs rapidly . Several clinical studies reported significant declines in parasite counts although total clearance was not achieved [25, 35]. The accurate assessment of parasite clearance requires high quality methods, which is why clinical studies not reporting such methods were excluded. Almost all of the trials reported symptom clearance in 60% or more of the patients, which suggests that traditional medicines are at least effective at relieving symptoms. The definition of “symptom clearance” also varied between studies so the figures reported are not necessarily comparable. Similarly, methods for ascertaining side-effects varied between trials, so the incidence figures are not comparable between trials. A checklist of possible side-effects  will inevitably generate a higher incidence of reports than asking an open question about side-effects, which was used in some other studies . Some of the symptoms reported may well have been due to the disease rather than to the treatment . In some of the clinical studies it is not clear whether patients were even asked about possible side-effects.
Clinical recovery and parasite clearance depend not only on the efficacy of the remedy but also on the level of immunity of the patient. All of the clinical studies took place in areas of intense seasonal transmission in sub-Saharan Africa, although the transmission season may have been shorter in the area where Bugmann’s study took place, so levels of immunity may have been lower there . Age is one of the major confounders and explains at least some of the differences between the studies. Several studies included only patients above the age of 12 [28, 29] or 18  and these tended to have better parasite clearance and adequate clinical response rates than the studies including younger children [30, 32, 35].
The correlation of the laboratory efficacy score with parasite clearance suggests that pre-clinical studies are useful predictors of clinical efficacy. There may be a publication bias because poor results are less likely to be published. However neither in vitro nor in vivo tests predicted all clinically useful remedies. Vernonia amygdalina (Asteraceae) had low in vitro activity but good in vivo activity (table 6). Argemone mexicana (Papaveraceae) did not show any activity in animals, although there was clear evidence of activity in vitro and in humans . A better correlation might be obtained by testing the anti-malarial activity in vitro of the serum of healthy volunteers having ingested the remedy , but this method has not been widely used. This would avert the problem of contaminating compounds such as saponins that complicate traditional testing of extracts in vitro.
The ethnobotanical score did not correlate with parasite clearance, but did correlate weakly with symptom clearance. This supports the view that traditional healers select plants which act on the symptoms, although not necessarily on the underlying cause of the disease. One limitation of the score is that for some plants the bulk of the ethnobotanical information is in documents which are unpublished or which are not included in international databases. A case in point is Artemisia annua (Asteraceae) which had the highest efficacy score and the best parasite clearance, but for which there is almost no ethnobotanical information in the international literature, so it had a very low ethnobotanical score. It was selected by the Chinese because of information in traditional Chinese texts, which are not catalogued in standard international databases. In fact another species (A. apiacea Hance) was used preferentially in ancient Chinese medicine, but it has never undergone clinical trials . Inclusion of national and local databases (especially Chinese) may improve the validity of the ethnobotanical score, but in practice this is difficult to do. Another concern is the influence of geographic range on the ethnobotanical score. Plants with a small geographic distribution do not have the opportunity to be cited in many studies. Cryptolepis sanguinolenta is one such plant, which is reported only in Ghana and in the Congo, but with a strong local reputation. Strong ethnomedical evidence, such as from a retrospective treatment-outcome study [8, 38], is probably a better predictor of efficacy than the number of citations. A revised score might take into account how extensively the plant is used across its distribution in malarious regions.
The safety component of the score was difficult to evaluate as few clinical trials contained quantitative information on incidence of side-effects, and furthermore clinical trials would only be done on plants which are well known to be non-toxic. The remedy with the lowest safety score (-5) was Cinchona bark, because of the reports of mild side-effects from use in humans , and because it contains potentially toxic alkaloids (including quinine). However, the clinical trials report that the incidence of side-effects from the bark was no greater than with the use of pure quinine . Therefore the presence of toxic compounds should perhaps be given less weight because toxicity always depends on dose and many effective medicines are toxic when excessive doses are given. The safety score is important to ensure toxic remedies are filtered out and not taken forward into clinical research, but there is a risk that it may screen out some of the most effective remedies that are toxic only at doses higher than the therapeutic dose, or have only mild and usually tolerable side-effects (such as Cinchona). For this reason it may be preferable to use a therapeutic index obtained in vivo by the ratio LD50/ED50. It is possible that a highly active plant would also be highly toxic, and so may receive a positive overall score. However it is very unlikely that an extremely hazardous plant would survive the test of time as a traditional medicine (or indeed that those taking it would survive or encourage others to use it), and this score is only intended for plants which are used as traditional medicines. Although it was not possible to validate the safety component of the score, safety is a very important consideration for prioritization of plants. In the absence of anything better we suggest that the safety score should be used as part of the selection process for prioritizing plants.
Another drawback of the score is that it is difficult to evaluate complex remedies which contain several plants. Most ethnobotanical studies report on uses of single plants rather than combinations, so that the ethnobotanical score would be low for such remedies. It is also rare for such combination remedies to be tested as such in vitro and in vivo. The only exception we found was “Malarial”, a combination of three plants used in Mali, which had undergone preclinical parasitological and safety tests prior to clinical trials and registration as an “improved traditional medicine” .
Although this scoring system was developed specifically to prioritize anti-malarial plants, it could be modified as a way of prioritizing plants for clinical trials on other diseases, although it would need to be validated again using relevant trials. The ethnobotanical component might be expected to be useful for diseases which are easily recognized traditionally, for example intestinal worms, dysentery, and skin ulcers. It would not be useful for diseases which have been newly discovered or which cannot be diagnosed without modern medical equipment (such as HIV/AIDS or Chagas disease). The efficacy component could however be adapted for any disease for which laboratory models exist, as a way of prioritising among many plants tested. The safety component could be applicable for any remedy (although we must stress that this part of the score could not be validated in our study).