Traditional herbal medicines for malaria
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《英国医生杂志》
1 Research Initiative for Traditional Antimalarial Methods (RITAM), Buckingham MK18 7EW, 2 Division of Medical Sciences, Medical Sciences Office, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU
Correspondence to: M Willcox merlinwillcox@doctors.org.uk
Introduction
The proportion of patients using traditional herbal remedies for malaria varies widely. A meta-analysis carried out by us of 28 studies on treatment seeking behaviour showed that 307 of 315 458 respondents used such remedies. The overall percentage was 20%, but this value is misleading because the range varied widely from 0% to 75%. Many factors influence the use of traditional medicines to treat malaria (see box).3
Plant species
Eighteen case studies have reported on herbal antimalarials. Of cohort studies mentioning herbal treatments, 17 were for falciparum malaria, 12 for vivax malaria, and 5 for malaria of undefined species. Table 3 provides details of 10 controlled trials of herbal preparations for uncomplicated malaria.
Table 3 Trials of herbal medicines for uncomplicated malaria
Often studies provided limited information on the methods used to prepare the remedies, making it difficult to replicate them. In some cases, this was deliberate, to protect intellectual property rights.4
Few studies (3 case studies, 13 cohort studies, 4 controlled trials) provided data on side effects. It seems that in the other studies, patients were not questioned about adverse effects or new symptoms since starting treatment. None of the studies reported serious adverse effects. Only three of the cohort studies and three of the controlled trials reported effects on biochemical variables (most commonly liver function tests), and two studies monitored electrocardiograms. No cases of toxicity were reported. Minor side effects can, however, be important. For example, almost half of the patients taking the Ugandan herbal remedy "AM" experienced one or more minor side effects.4 These were sufficiently unpleasant in some cases to deter patients from continuing treatment (for example, diarrhoea, bitter taste). Some herbal antimalarials have a bitter taste, making it difficult to give them to children. Doses often need to be taken repeatedly, and the volume may be larger than with conventional drugs.5
Six of the cohort studies on falciparum malaria reported 100% parasite clearance on days 4-7 after treatment, and a further three reported clearance rates above 90%. Follow up data beyond this time are available for only two of these nine studies, however, and only five of them studied more than 40 patients. One problem with cohort studies is that the trial population may be semi-immune to malaria and thus may clear parasites and resolve symptoms without effective treatment. High clearance rates may therefore not indicate efficacy. In highly endemic areas (as in much of sub-Saharan Africa), children aged over 5 years are considered to have a good immune response to malaria. In areas with high transmission of malaria, achieving complete parasite clearance for any length of time may not be realistic. In these circumstances, WHO recommends that adequate clinical response is a more useful measure of treatment efficacy. Such a response is defined as the absence of parasitaemia on day 14 or absence of fever (regardless of parasitaemia), without previously meeting the criteria for an early treatment failure.6
Influences on use of herbal antimalarials
Study design
Community compared with clinic (traditional or Western) setting
Questions asked (open or closed, retrospective or prospective) and by whom (community member or healthcare staff)
Definition of "malaria" or "fever"
Factors involved in treatment seeking behaviours
Perceived efficacy
Availability of traditional and Western medicines
Cost
Location: urban or rural
Age: adult or child
Some remedies may produce low rates of parasite clearance but higher rates of adequate clinical response. For example, in one study, parasitaemia declined to insignificant levels and patients were clinically cured after treatment with a decoction of Terraplis interretis.7 In another study, the Ugandan herbal remedy "AM" cleared parasites in only 8% of patients, but parasitaemia declined to lower levels, and 55% of patients had an adequate clinical response.4
Not all of the 10 controlled trials were randomised or double blind (table 3). Four trials of the Ayurvedic remedy Ayush-64 to treat vivax malaria were reported to be double blind because both the herbal preparation and the comparator drug were provided in identical capsules.5-8 Patients randomised to receive either herbal decoctions or chloroquine tablets cannot be blinded, but laboratory technicians who count the parasites can be, and in one trial they were blinded.9-10 Blinding was not reported for the other trials. One early trial was placebo controlled,11 which would now be considered unethical.
An aqueous root extract of Cryptolepis sanguinolenta shows promise in the treatment of falciparum malaria.12 Parasite clearance was only one day longer with this remedy than with chloroquine, and the clearance of fever was faster by 12 hours. A larger trial is needed to confirm these results, however, as the number of patients was small. In another trial comparing the treatment of falciparum malaria with quinine or with infusions of Artemisia annua, the infusions resulted in good parasite clearance at day 7.13 A high proportion of patients experienced a recrudescence, however, so that by day 28 only 37% of those treated with Artemisia annua were still free of parasites compared with 86% of patients treated with quinine. This emphasises the need for a follow up period of at least 28 days. Nevertheless, adequate clinical response, which is more important than parasite clearance in endemic areas,6 was not reported in this trial. In the trial of the herbal remedy "Malarial" (Suma-Kala), parasites were not cleared completely, but there was a good clinical response, which was sustained for the three weeks of follow up.9 10 In the trial of Cochlospermum tinctorium, patients were only followed for five days, and clinical outcomes were not used, so it is not possible to comment on long term efficacy.14
Five of the 10 controlled trials only studied vivax malaria, four of which concerned the herbal remedy "Ayush-64."5 8 Initial parasite clearance with Ayush-64 was good, but many patients relapsed by day 28. Another trial showed that oil based capsules of Artemisia annua cleared parasites and fever more rapidly than did chloroquine, and by day 30 only 8% of those given a course of capsules for six days showed recrudescence.15
Future research
Bodeker G, Willcox ML. Conference report: the first international meeting of the Research Initiative on Traditional Antimalarial Methods (RITAM). J Alternative Complementary Med 2000;6: 195-207.
Leaman DJ, Arnason JT, Yusuf R, Sangat-Roemantyo H, Soedjito H, Angerhofer CK, et al. Malaria remedies of the Kenyah of the Apo Kayan, East Kalimantan, Indonesian Borneo: a quantitative assessment of local consensus as an indication of biological efficacy. J Ethnopharmacol 1995;49: 1-16.
Willcox ML, Bodeker G, Rasoanaivo P. Traditional medicinal plants and malaria. Boca Raton: CRC, 2004.
Willcox ML. A clinical trial of `AM', a Ugandan herbal remedy for malaria. J Public Health Med 1999;21(3): 318-24.
Valecha N, Devi CU, Joshi H, Shahi VK, Sharma VP, Lal S. Comparative efficacy of Ayush-64 vs chloroquine in vivax malaria. Curr Sci 2000;78: 1120-2.
World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: WHO, 2003. (WHO/HTM/RBM/2003.50.)
Thiombiano A. Etudes des propriétés antipaludéenes de Terraplis interretis chez l'homme. Présentation au Séminaire CREDES, Paris, 4-9 Nov 1991.
Central Council for Research in Ayurveda and Sidhha. Ayush-64: a new antimalarial herbal compound. Delhi: CCRAS, 1987.
Koita N. A comparative study of the traditional remedy "Suma-Kala" and chloroquine as treatment for malaria in the rural areas. In: Mshigeni KE, Nkunya MHH, Fupi V, Mahunnah RLA, Mshiu E, eds. Proceedings of an international conference of experts from developing countries on traditional medicinal plants, Arusha, Tanzania, 18-23 Feb 1990. Dar Es Salaam: Dar Es Salaam University Press, 1991.
Guindo M. Contribution à l'étude du traitement traditionnel du "Suma" (Paludisme). PhD thesis, National School of Medicine and Pharmacy, Bamako, Mali, 1988.
Tsu CF. Chang Shan in the treatment of malaria. Trop Med Hygiene 1947;50: 75-7.
Boye GL. Studies on the antimalarial action of Cryptolepis sanguinolenta extract. Proceedings of an international symposium on East-West medicine, Seoul, Korea, 1989: 242-51.
Mueller MS, Runyambo N, Wagner I, Borrmann S, Dietz K, Heide L. Randomized controlled trial of a traditional preparation of Artemisia annua L (Annual Wormwood) in the treatment of malaria. Trans R Soc Trop Med Hygiene 2004;98(5): 318-21.
Benoit-Vical F, Valentin A, Da B, Dakuyo Z, Descamps L, Mallie M. N'Dribala (Cochlospermum planchonii) versus chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. J Ethnopharmacol 2003;89: 111-4.
Yao-De W, Qi-Zhong Z, Jie-Sheng W. Studies on the antimalarial action of gelatin capsule of Artemisia annua. Clin J Parasitol 1992;10(4): 290-4.
Kidane G, Morrow RH. Teaching mothers to provide home treatment of malaria in Tigray, Ethiopia: a randomised trial. Lancet 2000;356: 550-5.(Merlin L Willcox, secreta)
Correspondence to: M Willcox merlinwillcox@doctors.org.uk
Introduction
The proportion of patients using traditional herbal remedies for malaria varies widely. A meta-analysis carried out by us of 28 studies on treatment seeking behaviour showed that 307 of 315 458 respondents used such remedies. The overall percentage was 20%, but this value is misleading because the range varied widely from 0% to 75%. Many factors influence the use of traditional medicines to treat malaria (see box).3
Plant species
Eighteen case studies have reported on herbal antimalarials. Of cohort studies mentioning herbal treatments, 17 were for falciparum malaria, 12 for vivax malaria, and 5 for malaria of undefined species. Table 3 provides details of 10 controlled trials of herbal preparations for uncomplicated malaria.
Table 3 Trials of herbal medicines for uncomplicated malaria
Often studies provided limited information on the methods used to prepare the remedies, making it difficult to replicate them. In some cases, this was deliberate, to protect intellectual property rights.4
Few studies (3 case studies, 13 cohort studies, 4 controlled trials) provided data on side effects. It seems that in the other studies, patients were not questioned about adverse effects or new symptoms since starting treatment. None of the studies reported serious adverse effects. Only three of the cohort studies and three of the controlled trials reported effects on biochemical variables (most commonly liver function tests), and two studies monitored electrocardiograms. No cases of toxicity were reported. Minor side effects can, however, be important. For example, almost half of the patients taking the Ugandan herbal remedy "AM" experienced one or more minor side effects.4 These were sufficiently unpleasant in some cases to deter patients from continuing treatment (for example, diarrhoea, bitter taste). Some herbal antimalarials have a bitter taste, making it difficult to give them to children. Doses often need to be taken repeatedly, and the volume may be larger than with conventional drugs.5
Six of the cohort studies on falciparum malaria reported 100% parasite clearance on days 4-7 after treatment, and a further three reported clearance rates above 90%. Follow up data beyond this time are available for only two of these nine studies, however, and only five of them studied more than 40 patients. One problem with cohort studies is that the trial population may be semi-immune to malaria and thus may clear parasites and resolve symptoms without effective treatment. High clearance rates may therefore not indicate efficacy. In highly endemic areas (as in much of sub-Saharan Africa), children aged over 5 years are considered to have a good immune response to malaria. In areas with high transmission of malaria, achieving complete parasite clearance for any length of time may not be realistic. In these circumstances, WHO recommends that adequate clinical response is a more useful measure of treatment efficacy. Such a response is defined as the absence of parasitaemia on day 14 or absence of fever (regardless of parasitaemia), without previously meeting the criteria for an early treatment failure.6
Influences on use of herbal antimalarials
Study design
Community compared with clinic (traditional or Western) setting
Questions asked (open or closed, retrospective or prospective) and by whom (community member or healthcare staff)
Definition of "malaria" or "fever"
Factors involved in treatment seeking behaviours
Perceived efficacy
Availability of traditional and Western medicines
Cost
Location: urban or rural
Age: adult or child
Some remedies may produce low rates of parasite clearance but higher rates of adequate clinical response. For example, in one study, parasitaemia declined to insignificant levels and patients were clinically cured after treatment with a decoction of Terraplis interretis.7 In another study, the Ugandan herbal remedy "AM" cleared parasites in only 8% of patients, but parasitaemia declined to lower levels, and 55% of patients had an adequate clinical response.4
Not all of the 10 controlled trials were randomised or double blind (table 3). Four trials of the Ayurvedic remedy Ayush-64 to treat vivax malaria were reported to be double blind because both the herbal preparation and the comparator drug were provided in identical capsules.5-8 Patients randomised to receive either herbal decoctions or chloroquine tablets cannot be blinded, but laboratory technicians who count the parasites can be, and in one trial they were blinded.9-10 Blinding was not reported for the other trials. One early trial was placebo controlled,11 which would now be considered unethical.
An aqueous root extract of Cryptolepis sanguinolenta shows promise in the treatment of falciparum malaria.12 Parasite clearance was only one day longer with this remedy than with chloroquine, and the clearance of fever was faster by 12 hours. A larger trial is needed to confirm these results, however, as the number of patients was small. In another trial comparing the treatment of falciparum malaria with quinine or with infusions of Artemisia annua, the infusions resulted in good parasite clearance at day 7.13 A high proportion of patients experienced a recrudescence, however, so that by day 28 only 37% of those treated with Artemisia annua were still free of parasites compared with 86% of patients treated with quinine. This emphasises the need for a follow up period of at least 28 days. Nevertheless, adequate clinical response, which is more important than parasite clearance in endemic areas,6 was not reported in this trial. In the trial of the herbal remedy "Malarial" (Suma-Kala), parasites were not cleared completely, but there was a good clinical response, which was sustained for the three weeks of follow up.9 10 In the trial of Cochlospermum tinctorium, patients were only followed for five days, and clinical outcomes were not used, so it is not possible to comment on long term efficacy.14
Five of the 10 controlled trials only studied vivax malaria, four of which concerned the herbal remedy "Ayush-64."5 8 Initial parasite clearance with Ayush-64 was good, but many patients relapsed by day 28. Another trial showed that oil based capsules of Artemisia annua cleared parasites and fever more rapidly than did chloroquine, and by day 30 only 8% of those given a course of capsules for six days showed recrudescence.15
Future research
Bodeker G, Willcox ML. Conference report: the first international meeting of the Research Initiative on Traditional Antimalarial Methods (RITAM). J Alternative Complementary Med 2000;6: 195-207.
Leaman DJ, Arnason JT, Yusuf R, Sangat-Roemantyo H, Soedjito H, Angerhofer CK, et al. Malaria remedies of the Kenyah of the Apo Kayan, East Kalimantan, Indonesian Borneo: a quantitative assessment of local consensus as an indication of biological efficacy. J Ethnopharmacol 1995;49: 1-16.
Willcox ML, Bodeker G, Rasoanaivo P. Traditional medicinal plants and malaria. Boca Raton: CRC, 2004.
Willcox ML. A clinical trial of `AM', a Ugandan herbal remedy for malaria. J Public Health Med 1999;21(3): 318-24.
Valecha N, Devi CU, Joshi H, Shahi VK, Sharma VP, Lal S. Comparative efficacy of Ayush-64 vs chloroquine in vivax malaria. Curr Sci 2000;78: 1120-2.
World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: WHO, 2003. (WHO/HTM/RBM/2003.50.)
Thiombiano A. Etudes des propriétés antipaludéenes de Terraplis interretis chez l'homme. Présentation au Séminaire CREDES, Paris, 4-9 Nov 1991.
Central Council for Research in Ayurveda and Sidhha. Ayush-64: a new antimalarial herbal compound. Delhi: CCRAS, 1987.
Koita N. A comparative study of the traditional remedy "Suma-Kala" and chloroquine as treatment for malaria in the rural areas. In: Mshigeni KE, Nkunya MHH, Fupi V, Mahunnah RLA, Mshiu E, eds. Proceedings of an international conference of experts from developing countries on traditional medicinal plants, Arusha, Tanzania, 18-23 Feb 1990. Dar Es Salaam: Dar Es Salaam University Press, 1991.
Guindo M. Contribution à l'étude du traitement traditionnel du "Suma" (Paludisme). PhD thesis, National School of Medicine and Pharmacy, Bamako, Mali, 1988.
Tsu CF. Chang Shan in the treatment of malaria. Trop Med Hygiene 1947;50: 75-7.
Boye GL. Studies on the antimalarial action of Cryptolepis sanguinolenta extract. Proceedings of an international symposium on East-West medicine, Seoul, Korea, 1989: 242-51.
Mueller MS, Runyambo N, Wagner I, Borrmann S, Dietz K, Heide L. Randomized controlled trial of a traditional preparation of Artemisia annua L (Annual Wormwood) in the treatment of malaria. Trans R Soc Trop Med Hygiene 2004;98(5): 318-21.
Benoit-Vical F, Valentin A, Da B, Dakuyo Z, Descamps L, Mallie M. N'Dribala (Cochlospermum planchonii) versus chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. J Ethnopharmacol 2003;89: 111-4.
Yao-De W, Qi-Zhong Z, Jie-Sheng W. Studies on the antimalarial action of gelatin capsule of Artemisia annua. Clin J Parasitol 1992;10(4): 290-4.
Kidane G, Morrow RH. Teaching mothers to provide home treatment of malaria in Tigray, Ethiopia: a randomised trial. Lancet 2000;356: 550-5.(Merlin L Willcox, secreta)