Economically viable components from Jerusalem artichoke (Helianthus tuberosus L.) in a biorefinery concept.

Biorefinery applications are receiving growing interest due to climatic and waste disposal issues and lack of petroleum resources. Jerusalem artichoke (Helianthus tuberosus L.) is suitable for biorefinery applications due to high biomass production and limited cultivation requirements. This paper focuses on the potential of Jerusalem artichoke as a biorefinery crop and the most viable products in such a case. The carbohydrates in the tubers were found to have potential for production of platform chemicals, e.g., succinic acid. However, economic analysis showed that production of platform chemicals as a single product was too expensive to be competitive with petrochemically produced sugars. Therefore, production of several products from the same crop is a must. Additional products are protein based ones from tubers and leaves and biogas from residues, although both are of low value and amount. High bioactive activity was found in the young leaves of the crop, and the sesquiterpene lactones are of specific interest, as other compounds from this group have shown inhibitory effects on several human diseases. Thus, future focus should be on understanding the usefulness of small molecules, to develop methods for their extraction and purification and to further develop sustainable and viable methods for the production of platform chemicals.

Effect of artemisinin-based treatment policy on consumption pattern of antimalarials.

The purpose of this study was to observe the effect of the 2004 national artemisinin-based malaria treatment policy on consumption pattern of antimalarials. The study was undertaken at the University of Ilorin Teaching Hospital (UITH), Nigeria. Prescription and sales data at our pharmacy outlets were gathered from January to December 2004 and compared with similar data for 2005 after policy introduction in January 2005. Total consumption of antimalarials in 2004 was 23,404 doses, made up of artemisinin-containing medications (ACMs; 18.5%); sulphadoxine-pyrimethamine (SP; 7.1%); chloroquine (CQ; 72.85%); and quinine (QUI; 1.6%), compared with 26,383 doses in 2005, made up of ACMs (50.00%); SP (22.7%); CQ (27.3%); and QUI (0%). Z-tests indicate that these differences in proportions were significant (P < 0.001) for ACMs and SP (increased) and decreased for CQ and QUI. The comparative retail price per dose of these medications was in the order: ACMs > QUI > SP > CQ. These data show increased use of antimalarials, with ACMs overtaking CQ as the dominant antimalarial class purchased from the pharmacies operated by the hospital in the first year of policy implementation. This suggests that cost alone may not be the overriding determinant of specific antimalarial consumption.

Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

Operational response to malaria epidemics: are rapid diagnostic tests cost-effective?

OBJECTIVE: To compare the cost-effectiveness of malaria treatment based on presumptive diagnosis with that of malaria treatment based on rapid diagnostic tests (RDTs). METHODS: We calculated direct costs (based on experience from Ethiopia and southern Sudan) and effectiveness (in terms of reduced over-treatment) of a free, decentralised treatment programme using artesunate plus amodiaquine (AS + AQ) or artemether-lumefantrine (ART-LUM) in a Plasmodium falciparum epidemic. Our main cost-effectiveness measure was the incremental cost per false positive treatment averted by RDTs. RESULTS: As malaria prevalence increases, the difference in cost between presumptive and RDT-based treatment rises. The threshold prevalence above which the RDT-based strategy becomes more expensive is 21% in the AS + AQ scenario and 55% in the ART-LUM scenario, but these thresholds increase to 58 and 70%, respectively, if the financing body tolerates an incremental cost of 1 euro per false positive averted. However, even at a high (90%) prevalence of malaria consistent with an epidemic peak, an RDT-based strategy would only cost moderately more than the presumptive strategy: +29.9% in the AS + AQ scenario and +19.4% in the ART-LUM scenario. The treatment comparison is insensitive to the age and pregnancy distribution of febrile cases, but is strongly affected by variation in non-biomedical costs. If their unit price were halved, RDTs would be more cost-effective at a malaria prevalence up to 45% in case of AS + AQ treatment and at a prevalence up to 68% in case of ART-LUM treatment. CONCLUSION: In most epidemic prevalence scenarios, RDTs would considerably reduce over-treatment for only a moderate increase in costs over presumptive diagnosis. A substantial decrease in RDT unit price would greatly increase their cost-effectiveness, and should thus be advocated. A tolerated incremental cost of 1 euro is probably justified given overall public health and financial benefits. The RDTs should be considered for malaria epidemics if logistics and human resources allow.

The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets.

BACKGROUND: Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. METHODS: We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. RESULTS: 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be $1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00% of the Kenyan GDP. Fewer than 8% of all fevers were treated with an antimalarial drug within 24 hours of fever onset, while 17.5% were treated within 48 hours at a HCF. To achieve an increase from 17.5% to 33% of fevers treated with an antimalarial drug within 48 hours at a HCF (Scenario 1), children already being taken to a HCF would need to be taken earlier. Under this scenario, direct cash expenditures would not change, and total household costs would fall slightly to $1.86 because caretakers also save time with prompt treatment if the child has malaria. CONCLUSION: The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority.

Artemisinin-based combinations.

PURPOSE OF REVIEW: Artemisinin-based combination treatments have been the mainstay of treatment for falciparum malaria in Southeast Asia for more than 10 years and are now increasingly recommended as first-line treatment throughout the rest of the world. RECENT FINDINGS: A large multicentre randomised trial conducted in East Asia has shown a 35% reduction in mortality from severe malaria following treatment with parenteral artesunate compared with quinine. There is increasing evidence that artemisinin-based combination treatments are safe and rapidly effective. Artemether-lumefantrine (six doses) has been shown to be very effective in large trials reported from Uganda and Tanzania. A once daily three-dose treatment of dihydroartemisinin piperaquine, a newer fixed combination, was a highly efficacious and well tolerated treatment for multi-drug resistant falciparum malaria in Southeast Asia. SUMMARY: Early diagnosis and treatment of uncomplicated malaria with effective drugs remains a priority as part of a comprehensive malaria control strategy. Artemisinin-based combination treatments have consistently been shown to be highly effective and safe. The challenge is to make them accessible in tropical countries.

Differences in willingness to pay for artemisinin-based combinations or monotherapy: experiences from the United Republic of Tanzania.

OBJECTIVE: The cost of combination treatment is thought to be one of the greatest barriers to their deployment, but this has not been tested directly. Estimates of willingness to pay were compared across four drug combinations used to treat Tanzanian children with uncomplicated malaria. The reasons behind respondents' valuations and the effect of socioeconomic status on willingness to pay were explored. METHODS: One hundred and eighty mothers whose children had been recruited into a recently completed randomized effectiveness trial of amodiaquine + artesunate (AQ+AS), amodiaquine + sulfadoxine-pyrimethamine (AQ+SP), artemether-lumefantrine (coartemether) and amodiaquine monotherapy (AQ) were interviewed about their willingness to pay for these drugs two weeks after treatment. Estimates of willingness to pay were elicited with the bidding game technique. FINDINGS: A significant difference was detected in the mean amounts respondents were willing to pay, with those who received AQ+AS willing to pay the most, followed by co-artemether, AQ+SP and finally AQ. The amounts patients' mothers were willing to pay for the artemisinin-based combinations, however, fell well short of the market costs. Socioeconomic status was not found to have a statistically significant effect on mean willingness to pay scores for any treatment group. CONCLUSION: This study shows that families who live in an area in which drug resistance to monotherapy is very high are willing to pay more for more effective artemisinin-based combination therapies. These amounts, however, are nowhere near the real costs of delivering the new drugs. Only with subsidies will artemisinin-based combination therapies realistically have any impact.

Artemisinin-based combination therapy reduces expenditure on malaria treatment in KwaZulu Natal, South Africa.

INTRODUCTION: There is growing international evidence that artemisinin-based combination therapy (ACT) is one of the few effective measures available to 'Roll Back Malaria'. However, concerns about the costs and affordability of ACT are obstacles to its widespread implementation. This paper explores some economic aspects of the implementation of artemether-lumefantrine (AL) to replace sulphadoxine-pyrimethamine (SP) in the KwaZulu Natal (KZN) province, South Africa. METHODS: Recurrent and capital costs for malaria treatment were compared at baseline and post-intervention for nine clinics and a sentinel rural district hospital. Changes in the unit costs of, and total expenditure on, malaria services were calculated and the cost effectiveness of AL relative to SP was assessed. RESULTS: The number of outpatient malaria cases and inpatient admissions both declined by 94% between 2000 and 2002. After accounting for the role of concurrent improvements in vector control, it was conservatively estimated that 36% of the decline in outpatient cases and 46% for inpatient admissions was attributable to changing the first-line drug to AL. Although AL is considerably more expensive than SP, its improved cure rate and reduced malaria transmission resulted in an estimated 201,065 US dollars cost saving in 2002 alone for the subdistrict studied. DISCUSSION: In the context of effective vector control and low efficacy of existing monotherapy, ACT can reduce total expenditure on malaria services. However, the relevance of these findings requires careful consideration in countries with currently effective treatment policies and higher intensity malaria transmission.

Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices.

Increasing resistance of Plasmodium falciparum malaria to antimalarial drugs is posing a major threat to the global effort to "Roll Back Malaria". Chloroquine and sulfadoxine-pyrimethamine (SP) are being rendered increasingly ineffective, resulting in increasing morbidity, mortality, and economic and social costs. One strategy advocated for delaying the development of resistance to the remaining armory of effective drugs is the wide-scale deployment of artemisinin-based combination therapy. However, the cost of these combinations are higher than most of the currently used monotherapies and alternative non-artemisinin-based combinations. In addition, uncertainty about the actual impact in real-life settings has made them a controversial choice for first-line treatment. The difficulties in measuring the burden of drug resistance and predicting the impact of strategies aimed at its reduction are outlined, and a mathematical model is introduced that is being designed to address these issues and to clarify policy options.

A threshold analysis of the cost-effectiveness of artemisinin-based combination therapies in sub-saharan Africa.

Artemisinin-based combination therapies (ACTs) are generally regarded as vital in addressing the growing problem posed by the development of antimalarial resistance across sub-Saharan Africa. However, the costs of the new ACTs are likely to be significantly higher than current therapies. Therefore, it is important to examine formally the cost-effectiveness of the more effective yet more expensive ACTs before advocating a switch in policy. Importantly, any such economic evaluation must consider the temporal dynamics of drug resistance, and not just focus on the static question of whether switching today would be cost-effective at current levels of resistance, particularly since the development of new antimalarials in the future is so uncertain. However, predicting the future changes in drug resistance is a major difficulty in accurately quantifying the relative costs and health outcomes associated with different drug therapies over time. Here, we use a simple decision tree model to estimate the incremental cost-effectiveness of using ACTs, compared with persisting with current therapies, over 5-, 10-, and 15-year periods. We describe the dynamics of drug resistance using a general logistic growth function, in which the starting frequency of resistance and maximum growth may be altered. However, rather than make assumptions about the absolute rate at which resistance to ACTs will progress, we allow the ratio of the growth rate of resistance to ACTs relative to that of current therapies to vary. Defining the growth rate of ACT resistance in this manner allows us to calculate the threshold ratio at which ACTs would no longer appear cost-effective, for any starting conditions of resistance to current therapies and ACTs, and over any time period. The influence of uncertainty in other decision tree parameters on the threshold ratio values is also quantified, using Monte Carlo simulation techniques. This analysis shows that ACTs are more than 95% likely to be cost-effective under most conditions, other than very low levels of initial resistance to sulfadoxine/pyrimethamine and a five-year time frame. These predictions are conservative in that 95% certainty is a stringent decision rule favoring the rejection of new policies. The importance of other variables not included in the analysis for the robustness of the findings are discussed (e.g., consideration of the entire population at risk for malaria, the affordability of ACTs in specific settings, and the growth of resistance modeled according to population genetic parameters).