“Plant-based repellents have been used for generations in traditional practice as a personal protection measure against host-seeking mosquitoes. Knowledge on traditional repellent plants obtained through ethnobotanical studies is a valuable resource for the development of new natural products. Recently, commercial repellent products containing plant-based ingredients have gained increasing popularity among consumers, as these are commonly perceived as “safe” in comparison to long-established synthetic repellents although this is sometimes a misconception. To date insufficient studies have followed standard WHO Pesticide Evaluation Scheme guidelines for repellent testing. There is a need for further standardized studies in order to better evaluate repellent compounds and develop new products that offer high repellency as well as good consumer safety.”
Cymbopogon [Source: Wikimedia Commons, YosriNov04Pokok Serai]Noting that most plants contain compounds that they use in preventing attack from plant-eating insects including mosquitoes, Ferreira Maia and Moore review several plant-based insect repellents including lemon eucalyptus (Corymbia citriodora) extract, Cymbopogon nardus, Cymbopogon winterianus, neem (Azadirachta indica), and essential oils distilled from members of the Lamiaceae, Poaceae and Pinaceae families.
The authors address some fallacies about plant-based repellents and propose considerations for testing methodologies.
They conclude with a review of promising recent developments in research on plant-based repellents.
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
Curcuma longa [Source: Wikimedia Commons, J.M.Garg]Patrice N. Mimche of the London School of Hygiene and Tropical Medicine and Università di Milano, with coauthors Donatella Taramelli and Livia Vivas, review the properties of curcumin (Curcuma longa) and its potential as an adjunctive therapy for the management of cerebral malaria.
From the abstract:
“The clinical manifestations of cerebral malaria (CM) are well correlated with underlying major pathophysiological events occurring during an acute malaria infection, the most important of which, is the adherence of parasitized erythrocytes to endothelial cells ultimately leading to sequestration and obstruction of brain capillaries. The consequent reduction in blood flow, leads to cerebral hypoxia, localized inflammation and release of neurotoxic molecules and inflammatory cytokines by the endothelium. The pharmacological regulation of these immunopathological processes by immunomodulatory molecules may potentially benefit the management of this severe complication. Adjunctive therapy of CM patients with an appropriate immunomodulatory compound possessing even moderate anti-malarial activity with the capacity to down regulate excess production of proinflammatory cytokines and expression of adhesion molecules, could potentially reverse cytoadherence, improve survival and prevent neurological sequelae. Current major drug discovery programmes are mainly focused on novel parasite targets and mechanisms of action. However, the discovery of compounds targeting the host remains a largely unexplored but attractive area of drug discovery research for the treatment of CM.”
The authors review the evidence for curcumin as a modulator of the innate immune response to malaria infection, and conclude that the potential anti-malarial activity of curcumin merits investigation alongside ongoing research efforts exploring clinical applications of curcumin in chronic inflammatory disorders, diabetes and cancer.
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
“The outcomes from recent high profile deliberations concerning African health research and economic development all point towards the need for a mechanism to support health innovation on the continent. The mission of the African Network for Drugs and Diagnostics Innovation (ANDI), is to promote and sustain African-led health product innovation to address African public health needs through the assembly of research networks, and building of capacity to support human and economic development. ANDI is widely viewed as the vehicle to implementing some of these recommendations. There is tremendous opportunity for Africa, to leverage the expertise in natural products and traditional medicines in support of this objective to kick-start innovation. This report highlights key recommendations that have emerged through expert forums convened by ANDI on the challenges, opportunities and prospects for investing in this important area of research.”
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
“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.”
Noting that “conventional drug development is slow and expensive, taking up to 15 years and up to $800m to develop a new drug,” and that “the finished products are often unavailable and unaffordable to the poorest patients in remote areas, unless they are part of a heavily subsidized scheme,” the team hypothesized that development of standardized phytomedicines in parallel with conventional drug development might prove to be a faster, cheaper, and more sustainable approach for remote areas where malaria is endemic.
Reverse pharmacology was originally developed in India and China in the Mid-20th Century to make use of Ayurvedic and Traditional Chinese whole systems of medicine while at the same time employing the conventional pharmaceutical pathway of isolating compounds for further development.
Argemone mexicana [Source: Wikimedia Commons user B.navez]The team developed and tested a reverse pharmacology pathway using a traditional herbal medicine derived from Argemone mexicana, a pan-tropical weed found in many places where malaria is endemic. In contrast to the conventional pharmaceutical pathway, the reverse pharmacology process took six years and cost about 400,000 Euros.
At the time of writing, the new antimalarial phytomedicine developed from the Argemone mexicana decoction was in the process of being approved in Mali.
The reverse pharmacology pathway had four discrete stages:
Selection of a herbal remedy
Dose-escalating clinical study
Randomized controlled trial
Isolation and testing of active compounds
In addition to the Argemone mexicana phytomedicine, the authors report that other phytomedicines for malaria have already been developed and are government-approved in Burkina Faso (Cochlospermum planchonii root decoction), in Ghana (Cryptolepis sanguinolenta root infusion) and in the Democratic Republic of Congo (Artemisia annua Anamed leaf infusion).
The authors recommend that funding organizations “support the possibility of developing new types of medicines, including phytomedicines, rather than restricting funding only to conventional development of isolated active compounds,” with sustainable public health improvement in remote areas as a key consideration.
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
Noting that more than 1,200 plant species are reported in ethnobotanical studies for the treatment of malaria and fevers, the authors stress the importance of prioritizing plants for further development of antimalarial medicines, especially considering the very limited funds available for research.
The Research Initiative on Traditional Anti-malarial Methods (RITAM) was founded in 1999 to review current knowledge on traditional antimalarial methods in order to help determine research priorities, design optimal research methodologies, and avoid replication of research.
“There already exists a wealth of published ethnobotanical and pharmacological studies on anti-malarial plants. However, this information has never been reviewed systematically and there is no standard method for doing so. Standard scores and methods have been developed for meta-analysis of studies of medical interventions and diagnostic tests. There have been attempts at scoring plants according to basic ethnobotanical criteria (for example frequency of citation, or how widely a remedy is used but these do not take into account all important factors such as the quality of studies or pharmacological information on efficacy and safety. Others have prioritized plants according to the selectivity index in vitro, corresponding to the ratio between cytotoxicity and activity against Plasmodium falciparum. The first aim of this study was to design a standard score that could be used to prioritize traditional herbal remedies for further research based on objective criteria and systematic literature reviews, combining all available information from both ethnobotanical and pharmacological studies. The second aim was then to pilot this score and assess its ability to predict results of clinical trials for the few plant remedies that have been tested clinically for the treatment of malaria.”
The authors note severe limitations of the RITAM scoring method in its present state; for example:
“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).”
They conclude with a hope that the scoring method and its validation might be improved with more clinical studies of herbal antimalarials.
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
“Should traditional medicine be officially considered and recommended as complementary or alternative solutions in malaria control programs? And, if so, under what conditions?”
Noting that herbal compounds provided important leads for two modern antimalarials, quinine and artemisinin, the authors highlight several other traditional medicines for malaria where laboratory research and an increasing body of clinical research has shown evidence of effectiveness malaria control.
The authors discuss studies in Tanzania, Ghana and Mauritania showing improvement in the management of severe malaria through a collaboration between traditional healers and modern health care providers, forming a natural extension of the formal health service and improving access to modern medicines by the willingness of traditional practitioners to refer patients with severe malaria to their modern counterparts – e.g., for participation in clinical trials as appropriate.
Based on their review and field experience, the team proposes a project to incorporate traditional medicine into malaria control programs, organized along the following lines:
Recognize traditional medicine as a (sometimes) valuable health resource, on the basis of published research
Foster working relationships with those using traditional medicine
Search for safe and effective local traditional medicines
Spread results for clinical recommendations
Make traditional medicine part of the public health system
Explore the potential for traditional medicines as candidates for lead chemical compounds and drug development
In their conclusion, the authors note that the WHO Regional Committee for Africa Strategy for Promoting Traditional Medicine includes the development of local production and conservation of medicinal plants, legislation of traditional medicine practice and its integration into conventional health services.
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
With a review of the published literature “to establish the responsibility of isolated active compound(s) to the whole antiplasmodial activity of a crude extract,” Eric Deharo of the Université de Toulouse and Institut de Recherche pour le Développement and supplement editor Hagai Ginsburg lend support to the argument of Rasoanaivo et al., namely, that the antiplasmodial activity of isolated molecules do not account on their own for the activity of plant extracts.
Reviewing 1,031 articles describing the antiplasmodial activity of plant extracts posted on PubMed for the past 10 years, Deharo and Ginsburg found that “only a very few included the activity of the whole extract and of the pure compounds and their respective yields of extraction.” However, for most of the plants studied in those few papers, the anti-malaria activity of the purified compounds could not account quantitatively for that of the crude extract.
They conclude:
“If indeed this observation reflects the reality of anti-malarial properties of plant extracts, may be research should be focused on the “drug beside the drug”, looking for structures perhaps not exciting in the chemical point of view but that can revolutionize the treatment of malaria. Another natural consequence of this analysis is that evolution has provided not only bioactive metabolites that plants use to fight their foes, but has also mixed them in a very auspicious combination of compounds, which in some cases also work well in mammals. To achieve a similar combination even by systematic bioguided mixing is a very tedious, lengthy and expensive procedure. Why not learn from nature and optimize the use of plant extracts?”
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
“There 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.”
Rasoanaivo and his coauthors posit an evolutionary basis and possible mechanisms for pharmacodynamic synergy observed in crude extracts, and review evidence for the effect in traditional antimalaria products from a number of countries where malaria is endemic.
They recommend clinical trials of these products, including curcumin and Cinchona bark, and combinations of products (such as Artemisia annua leaves + Curcuma longa root + Piper nigum seeds).
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
Timothy NC Wells of MMV: Medicines for Malaria Venture reviews the history of “natural product scaffolds” that “have been the basis of the majority of current anti-malarial medicines” and recommends a change of approach in the search for new antimalarials:
“The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective [from] many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.”
Specifically, Wells proposes better exploitation of a key strategic advantage of herbal antimalarials; i.e., “that in several cases we know that there is an activity in patients”:
“Once the clinical activity of a herbal medicinal product is verified in observational studies, the anti-parasitic activity of the plasma samples on parasites could be confirmed ex vivo, and characterization of the decoction and the plasma samples using mass spectrometry and HLPC separations. Once the active ingredients are identified it is likely that medicinal chemistry will be needed to optimize it for clinical use.”
“By making the most of the potential for clinical data,” Wells concludes, “It is possible that [natural products] could continue to influence our thinking for the next century.”
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
Eric Guantai and Kelly Chibale of the University of Cape Town begin by noting that “other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years”:
“Unfortunately the current reality is that other than compounds that have their foundation in historic natural products (such as quinine, artemisinin, hydroxynaphthoquinones, doxycyclin, clindamycin, and azithromycin), there are no other compounds in preclinical development or further that have originated from a natural product start-point in recent years. There are not even any compounds in current anti-malarial lead optimization projects that have come from natural products in recent years. Many natural products have shown potent anti-plasmodial effects but, for a variety of reasons, including chemical tractability issues, these have not been pushed forward into hit-to-lead drug discovery projects.”
Guantai and Chibale then review several approaches from outside the field of malaria that “could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds,” including: drug combinations; dual drugs/drug hybrids; metabolism and metabolite identification studies; molecular modeling and docking tools; natural product-derived pharmacophores (group of atoms in the molecule responsible for the drug’s action) and template-based virtual screening; natural product databases; and target-identification and reverse pharmacology.
Citing evidence from these approaches of “the potential of natural products to provide or inspire the development of anti-malarial lead compounds,” the authors recommend collaboration across diverse scientific disciplines in the search for novel agents for development:
“The potential of natural products to provide or inspire the development of anti-malarial lead compounds is, therefore, really quite evident. However, to raise the chances of the actual realization of this potential, it has become necessary to think beyond the confines of conventional natural-product drug discovery. The application of a wide variety of scientific tools and the close and interactive collaboration of experts in diverse scientific disciplines (such as chemistry, pharmacology, molecular biology and genetics) has become practically obligatory if these truly multi-disciplinary efforts are to indeed be successful. The fact that literature on the application of some of these approaches towards anti-malarial drug discovery based on natural products is sparse is indicative of their underutilization in this regard, a situation that should arguably be addressed.”
The information on my blog is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition.
