It is common belief and a dogma of the Western school medicine that valid results with the extracts of natural products can only be obtained if individual constituents are isolated and purified to the highest grade. This entails that most, if not all, scientific papers describing research in this field are based on monotherapies with ultrapure products.
The basic reason of this approach is that Bigpharma can only sell drugs with a high purity; in order to gain approval and access to the market they need to pass the hurdle of clinical trials based on monotherapies of pure products.
Biosynthetic pathways endow nature’s library of chemicals with an evolutionary advantage over man-made chemicals. Natural product libraries continue to be an important and attractive source for new therapeutic agents. But nature never uses isolated pure products. There is evidence that crude plant extracts often have greater in vitro or/and in vivo 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.
It appears more and more that ultrapurity is a flawed approach because it ignores several factors which control the efficiency of a drug. Synergy or antagonism between different constituents, higher solubility and bioavailabity of an active molecule of an herb in a decoction, or the simple interaction of inorganic ions with organic molecules in solution.
The first one to address this critical issue in a research program was Frank van der Kooy, Natural Products Laboratory, Institute of Biology, Leiden University, in a study of Artemisia annua tea infusions. The plant material of Artemisia , and the tea infusion thereof, contains many different compounds including the active principle artemisinin. They have shown that by using specific preparation methods for the tea infusion it is possible to extract up to 95% of the artemisinin present in the plant material. The co-extracted compounds in the tea infusion can have a synergistic effect on many different levels against Plasmodium falciparum, for example: Stimulating the immune system, inhibiting secondary infections, affect the physical properties of the infection site , affecting non-lethal biochemical processes in P. falciparum (e.g. efflux channel inhibitors), having a direct activity against P. falciparum but at a different target site, improving the bioavailability of the active compound etc. To prove synergism is very difficult, due to its inherent complexity and the fact that assays are predominantly done in vitro. The method of use can potentially add another layer of complexity to the problem. During preparation of the tea infusion deionised water is used in the laboratory (acidic pH, low electrical conductivity) whilst people using the tea as a treatment use any locally available water (e.g. tap, borehole, river, rain water etc). The water chemistry will therefore be drastically different depending on the source of water.
Van der Kooy, F., Verpoorte, R., 2011. The Content of Artemisinin in the Artemisia annua Tea Infusion. Planta Medica. 77, 1754–1756.
Frank van der Kooy, Julia Mouton., PO Box 9502, 2333 CC Leiden. Unlocking the full (medicinal) potential of Artemisia annua: A LC-MS and NMR investigation of the tea infusion. Unpublished paper, personal communication
The inhibition of hemozoin formation is a key mechanism explaining the efficacy of the antimalarials like quinine or chloroquine. The parasite tries to eliminate by crystallization the toxic heme resulting from the hemoglobin digestion in the parasite vacuole. Artemisia plant infusions or powders have a strong inhibitory effect, artemisinin does not. The university of Al Quds, Palestine, found that the addition of sodium chloride or sodium bicarbonate enhanced the beta-hematin inhibition properties of Artemisia infusions.
Suhair Jaber, Saleh Abu-Lafi, Pierre Lutgen, Mutaz Qutob, Qassem Abu-Remeleh and Mutaz Akkawi. Bicarbonate in in vitro effect on beta-hematin inhibition by Artemisia sieberi aqueous infusion. Journal of Pharmacy and Pharmacology, 2015 3, 63-72.
They also found that the individual substances zinc and arginin do not inhibit beta-hemation formation but that the aqueous mixture of the two well does (personal communication),
There is also the breakthrough work of Pamela Weathers. Her team found that a single dose of whole leaf dried powder of Artemisia annua (containing 24 mg/kg artemisinin) reduces parasitemia more effectively than a comparable dose of purified drug. This increased efficacy may result from a documented 40-fold increase in the bioavailability of artemisinin in the blood of mice fed the whole plant, in comparison to those administered synthetic drug. Synergistic benefits may derive from the presence of other anti-malarial compounds in Artemisia annua. If shown to be clinically efficacious, well-tolerated, and compatible with the public health imperative of forestalling evolution of drug resistance, inexpensive, locally grown and processed Artemisia annua might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality.
Elfawal MA, Towler MJ, Reich NG, Golenbock D, Weathers PJ, et al. (2012) Dried Whole Plant Artemisia annua as an Antimalarial Therapy. PLoS ONE 7(12): e52746. doi:10.1371/journal.pone.0052746
Weathers has continued her research along these lines and shown that dried whole-plant Artemisia annua slows evolution of malaria drug resistance and even overcomes resistance to artemisinin and its derivatives, resistance which is spreading from Asia to Africa.
Mostafa A. Elfawal, Melissa J. Towler, Nicholas G. Reich, Pamela J. Weathers, and Stephen M. Rich, PNAS 2014, 1413127112 Artemisia annua dried leaf tablets treated malaria resistant to ACT and i.v.artesunate: Case reports Nsengiyumva Bati Daddy, Luc Malemo Kalisya , Pascal Gisenya Bagire, Rober tL.Watt, Melissa J.Towler, Pamela J.Weathers. Phytomedicine 2017.
The study from another team showed the complexities of these interactions. Artemisia annua hot water infusion (tea) was used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. The results of these in vitro tests and of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from Artemisia annua with significant anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain. In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B 's potentiation of artemisinin.
Suberu JO, Gorka AP, Jacobs L, Roepe PD, Sullivan N, Barker GC, Lapkin AA. Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract--possible synergistic and resistance mechanisms. PLoS One. 2013 Nov 14;8(11):e80790. doi: 10.1371/journal.pone.0080790. eCollection 2013
But the best evidence that these interactions play a key role and that pure monosubstances are not necessarily the ultimate in therapy were obtained in a Swiss study. This piece of work shows that the isolation of individual ingredients from a plant for the purposes of being able to control them better or for commercial benefit does not always lead to the desired therapeutic objective. The study explored the variability of biological responses from the perspective of sample purity and introduces the concept of purity−activity relationships (PARs) in natural product research. The abundant plant triterpene ursolic acid was selected as an exemplary natural product due to the overwhelming number yet inconsistent nature of its approximate 120 reported biological activities, which include anti-TB potential. Nine different samples of ursolic acid with purity certifications were obtained, and their purity was independently assessed by means of quantitative NMR. Biological evaluation consisted of determining MICs against two strains of virulent Mycobacterium tuberculosis and IC50 values in Vero cells. The results imply that synergistic effects of ursolic acid and its varying impurities are the likely cause of previously reported antimycobacterial potential. Minute traces of impurities therefore obviously produced a better effect against tuberculosis bacteria. Or, to put it in a nutshell: Without impurities, the preparation had no effect! .
See the original graph in the following paper.
Birgit U. Jaki, Scott G. Franzblau, Lucas R. Chadwick, David C. Lankin, Fangqiu Zhang, Yuehong Wang and Guido F. Pauli. Purity−Activity Relationships of Natural Products: The Case of Anti-TB Active Ursolic Acid. J. Nat. Prod., 2008, 71 (10), pp 1742–174
Similar results on the purity activity relationship PAR were obtained in another study for triterpenes.
Qiu F, Cai G, Jaki BU, Lankin DC, Franzblau SG, Pauli GF. Quantitative purity-activity relationships of natural products: the case of anti-tuberculosis active triterpenes from Oplopanax horridus. . J Nat Prod. 2013 Mar 22;76(3):413-9. doi: 10.1021/np3007809. Epub 2013 Jan 28.
Or for the constituents of pomegranate juice. The superior bioactivity of the juice itself compared to its purified polyphenols illustrates the multifactorial effects of the action of multiple compounds compared to single purified active ingredients.
Navindra P Seeram, Lynn S Adams, Susanne M Henning, Yantao Niu, Yanjun Zhang, Muraleedharan G Nair, David Heber. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. The Journal of nutritional biochemistry 2005 16, 360-7
Antagonism and synergy are of utmost importance in cancer treatment. Results from several studies indicate that the anticarcinogenic potential of foods containing polyphenols may not be based on the effects of individual compounds, but may involve a synergistic enhancement of the anticancer effects.
Mertens-Talcott SU, Percival SS. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett. 2005 Feb 10;218(2):141-51.
The detrimental effect of Vitamin E on the efficacy of antimalarial drugs is well known, the one of Vitamin C to a lesser extent. The malaria belt of the world (tropical regions) with rich sources of vitamin C constitutes malaria endemic zones. In these zones, where vitamin C rich food such as citrus fruits and green vegetables abound, a mutual relationship between the two appears to exist.
A database of vitamin C contents in tropical vegetables and foods has been published. Moringa oleifera for example contains 7 times more vitamin C than oranges. Moringa has no antimalarial properties and may even enhance a malaria infection.
M. Ogunlesi, W. Okiei, L. Azeez, V. Obakachi, M. Osunsanmi, G. Nkenchor. Vitamin C Contents of Tropical Vegetables and Foods Determined by Voltammetric and Titrimetric Methods and their Relevance to the Medicinal Uses of the Plants. Int J Electrochem Sci 2010, 5, 105-115.
Another example are interferences between aspirin, paracetamol and antimalarial drugs. Aspirin (acetylsalicylic acid) is sold over the counter in Africa and appears to be the first line treatment when children or adults have fever. Chronic salicylate poisoning by overdosis is common. In all children admitted to Kilifi District Hospital between July and September 1994, who had a positive blood film for Plasmodium falciparum, and one or more of coma, prostration, or respiratory distress salicylate concentrations were measured. Data were available for 143 children with initial primary diagnoses of severe malaria. 129 had detectable (>l mg/dL) salicylate. Six of these had salicylate concentrations of 20 mg/dL or higher. All six had neurological impairment and metabolic acidosis and four were, or became, hypoglycaemic. OTC drugs were the first-line treatment in 74 percent of the patients. 21 percent of the mothers gave a dose higher than the manufacturer's recommended maximum. These cases suggest that in some children salicylate poisoning may cause or contribute to the development of metabolic acidosis and hypoglycaemia, complications of severe malaria associated with high mortality.
English M, Marsh V, Amukoye E, Lowe B, Murphy S, Marsh K. Chronic salicylate poisoning and severe malaria. Lancet. 1996 Jun 22;347(9017):1736-7.