Cost-comparison of DDT and alternative insecticides for malaria control

In anti-malaria operations the use of DDT for indoor residual spraying has declined substantially over the past 30years, but this insecticide is still considered valuable for malaria control, mainly because of its low cost relative to alternative insecticides. Despite the development of resistance to DDT in some populations of malaria vector Anopheles mosquitoes (Diptera: Culicidae), DDT remains generally effective when used for house-spraying against most species of Anopheles, due to excitorepellency as well as insecticidal effects. A 1990 cost comparison by the World Health Organization (WHO) found DDT to be considerably less expensive than other insecticides, which cost 2 to 23 times more on the basis of cost per house per 6 months of control. To determine whether such a cost advantage still prevails for DDT, this paper compares recent price quotes from manufacturers and WHO suppliers for DDT and appropriate formulations of nine other insecticides (two carbamates, two organophosphates and five pyrethroids) commonly used for residual house-spraying in malaria control programmes. Based on these 'global' price quotes, detailed calculations show that DDT is still the least expensive insecticide on a cost per house basis, although the price appears to be rising as DDT production declines. At the same time, the prices of pyrethroids are declining, making some only slightly more expensive than DDT at low application dosages. Other costs, including operations (labour), transportation and human safety may also increase the price advantages of DDT and some pyrethroids vs. organophosphates and carbamates, although possible environmental impacts from DDT remain a concern. However, a global cost comparison may not realistically reflect local costs or effective application dosages at the country level. Recent data on insecticide prices paid by the health ministries of individual countries showed that prices of particular insecticides can vary substantially in the open market. Therefore, the most cost-effective insecticide in any given country or region must be determined on a case-by-case basis. Regional coordination of procurement of public health insecticides could improve access to affordable products.     

Entomopathogenic fungi as biological insecticides to control malaria

Malaria is arguably the most serious vector-borne disease worldwide. The already-alarming number of deaths caused by malaria is increasing, caused in part by the increase in mosquito resistance to chemical insecticides. In two recent articles, the use of an approach was reported that could open a new front in the fight against malaria. Laboratory and field studies demonstrate that entomopathogenic fungi can efficiently kill adult anopheline mosquitoes, the females of which are the obligatory vectors for malaria parasites.     

Interactions between malaria parasites and their mosquito hosts in the midgut

This review examines what is presently known of the molecular interactions between Plasmodium and Anopheles that take place in the latter's midgut upon ingestion of the parasites with an infectious blood meal. In order to become 'established' in the gut and to transform into a sporozoite-producing oocyst, the malaria parasite needs to undergo different developmental steps that are often characterized by the use of selected resources provided by the mosquito vector. Moreover, some of these resources may be used by the parasite in order to overcome the insect host's defence mechanisms. The molecular partners of this interplay are now in the process of being defined and analyzed for both Plasmodium and mosquito and, thus, understood; these will be presented here in some detail.     

Barcoded Asaia bacteria enable mosquito in vivo screens and identify novel systemic insecticides and inhibitors of malaria transmission

This work addresses the need for new chemical matter in product development for control of pest insects and vector-borne diseases. We present a barcoding strategy that enables phenotypic screens of blood-feeding insects against small molecules in microtiter plate-based arrays and apply this to discovery of novel systemic insecticides and compounds that block malaria parasite development in the mosquito vector. Encoding of the blood meals was achieved through recombinant DNA-tagged Asaia bacteria that successfully colonised Aedes and Anopheles mosquitoes. An arrayed screen of a collection of pesticides showed that chemical classes of avermectins, phenylpyrazoles, and neonicotinoids were enriched for compounds with systemic adulticide activity against Anopheles. Using a luminescent Plasmodium falciparum reporter strain, barcoded screens identified 48 drug-like transmission-blocking compounds from a 400-compound antimicrobial library. The approach significantly increases the throughput in phenotypic screening campaigns using adult insects and identifies novel candidate small molecules for disease control.

This study presents a barcoding strategy that enables high-throughput phenotypic screens of blood-feeding insects against small molecules in microtiter plate-based arrays and applies this to the discovery of novel systemic insecticides and compounds that block malaria parasite development in the mosquito vector.     

Evaluation of certain insecticides on nettings for their efficacy and wash resistance against mosquito species

Five insecticides (Bifenthrin, Deltamethrin, Etofenprox, Permethrin and Lamda cyhalothrin) recommended by WHO, at their recommended dose were compared for their efficacy and wash resistance through bioassay against mosquito vectors, Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi. Etofenprox treated nettings exhibited better knockdown and mortality than the other insecticides. The order of efficacy of the insecticides treated nettings was Etofenprox > or = Deltamethrin > Lambda cyhalothrin > Permethrin > Bifenthrin.     

Bisquinoline antimalarials: their role in malaria chemotherapy.

Quinoline compounds, such as chloroquine, are used widely to treat malaria; however, the malarial parasite is rapidly becoming resistant to the drugs currently available. Presently, rational drug design is hindered considerably due to the mode of action of chloroquine being poorly understood. We rely on serendipity, rather than solid structural evidence, to generate new antimalarials. Hence any insight into the possible modes of action of quinoline antimalarials, including the bisquinolines, would greatly aid rational drug design. The quinoline antimalarial drugs, chloroquine, quinine and mefloquine, are thought to act by interfering with the digestion of haemoglobin in the blood stages of the malaria life-cycle. These quinoline antimalarials traverse down the pH gradient to accumulate to millimolar concentrations in the acidic vacuole of the parasite. It has been suggested that this high intravacuolar concentration prevents haem sequestration, causing a build up of the toxic haem moiety and the death of the parasite by its own toxic waste. The actual mechanism by which the parasite sequesters haem and the drug target(s) during this process, however, still remains elusive. As a consequence, haem polymerisation and the efficiency of quinoline antimalarials, including the bisquinolines, as inhibitors of this process has been investigated. In this paper, the potential role of the bisquinolines in the fight against chloroquine-resistant malaria is addressed.     

Oogenesis in the malaria mosquito Anopheles gambiae

Summary Oogenesis has been followed with the electron microscope in 2 strains of the malaria mosquito Anopheles gambiae, from the emergence of the adult (oocytes at leptonema) till shortly before the oocytes are ready for oviposition. After pachynema the chromosomes form a karyosphere and a fibrous capsule develops around it. Work on other mosquitoes suggests that the capsule may be related to the synaptonemal complexes. Both Anopheles strains contain at some time an extrachromosomal (not DNA-containing) body comparable to the karyosphere in size. Clusters of granules are present at the surface of the nucleolus and free in the nucleoplasm. Tentative results indicate that they may contain DNA. During oogenesis the nucleolus becomes very large, mainly because of proliferation of the nucleolonema. Towards the end of oocyte development the nucleus assumes the large canoe-shape also seen in Aedes and Culex. Nucleolonema traverse the entire nucleus, and modified granular clusters are found throughout.     

Effect of mosquito contact with DDT and their susceptibility to the causative agent of malaria

The contact of Aedes aegypti mosquitoes with DDT one hour prior to the infectious feeding results in a slight decrease of their susceptibility to Plasmodium gallinaceum. The contact 24 hours prior to the infectious feeding does not affect the susceptibility of mosquitoes.     

New repellent effective against African malaria mosquito Anopheles gambiae: implications for vector control

Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) is a vector for Plasmodium, the causative agent of malaria. Current control strategies to reduce the impact of malaria focus on reducing the frequency of mosquito attacks on humans, thereby decreasing Plasmodium transmission. A need for new repellents effective against Anopheles mosquitoes has arisen because of changes in vector behaviour as a result of control strategies and concern over the health impacts of current repellents. The response of A. gambiae to potential repellents was investigated through an electroantennogram screen and the most promising of these candidates (1‐allyloxy‐4‐propoxybenzene, 3c {3,6}) chosen for behavioural testing. An assay to evaluate the blood‐host seeking behaviour of A. gambiae towards a simulated host protected with this repellent was then performed. The compound 3c {3,6} was shown to be an effective repellent, causing mosquitoes to reduce their contact with a simulated blood‐host and probe less at the host odour. Thus, 3c {3,6} may be an effective repellent for the control of A. gambiae.     

Large-scale use of mosquito larval source management for malaria control in Africa: a cost analysis

Background

At present, large-scale use of two malaria vector control methods, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) is being scaled up in Africa with substantial funding from donors. A third vector control method, larval source management (LSM), has been historically very successful and is today widely used for mosquito control globally, except in Africa. With increasing risk of insecticide resistance and a shift to more exophilic vectors, LSM is now under re-evaluation for use against afro-tropical vector species. Here the costs of this intervention were evaluated.

Methods

The 'ingredients approach' was used to estimate the economic and financial costs per person protected per year (pppy) for large-scale LSM using microbial larvicides in three ecologically diverse settings: (1) the coastal metropolitan area of Dar es Salaam in Tanzania, (2) a highly populated Kenyan highland area (Vihiga District), and (3) a lakeside setting in rural western Kenya (Mbita Division). Two scenarios were examined to investigate the cost implications of using alternative product formulations. Sensitivity analyses on product prices were carried out.

Results

The results show that for programmes using the same granular formulation larviciding costs the least pppy in Dar es Salaam (US$0.94), approximately 60% more in Vihiga District (US$1.50) and the most in Mbita Division (US$2.50). However, these costs are reduced substantially if an alternative water-dispensable formulation is used; in Vihiga, this would reduce costs to US$0.79 and, in Mbita Division, to US$1.94. Larvicide and staff salary costs each accounted for approximately a third of the total economic costs per year. The cost pppy depends mainly on: (1) the type of formulation required for treating different aquatic habitats, (2) the human population density relative to the density of aquatic habitats and (3) the potential to target the intervention in space and/or time.

Conclusion

Costs for LSM compare favourably with costs for IRS and LLINs, especially in areas with moderate and focal malaria transmission where mosquito larval habitats are accessible and well defined. LSM presents an attractive tool to be integrated in ongoing malaria control effort in such settings. Further data on the epidemiological health impact of larviciding is required to establish cost effectiveness.     

Rate effectors and their role in metabolic control

On the basis of control theory, it is suggested that two kinds of allosteric effects can be distinguished; in one kind a rate-limiting enzyme is sensitive to the concentration of an end-product, while in the other a rate-limiting enzyme is affected by the rate at which an end-product is consumed. In the first case the effector is the end-product of the pathway, while in the second case the effector is a coenzyme derivative of the end-product, and is designated a rate-effector. Coenzymes (e.g. ATP, NADH) which appear to provide a measure of some aggregate of metabolic performance, might also be regarded as rate-effectors.     

Phrenic afferents and their role in inspiratory control

In anesthetized cats, with vagi cut and the spinal cord severed at the C8 level, phrenic motor and/or sensory discharge was recorded. Small afferent phrenic fibers were identified through their activation by lactic acid, hyperosmotic NaCl solution, or phenyl diguanide. They exhibited a spontaneous but irregular low-frequency discharge. Block of their conduction by procaine had no effect on eupneic motor phrenic activity. Large afferent phrenic fibers showed a spontaneous rhythmic discharge, and cold block (6 degrees C) of these fibers significantly prolonged the phrenic discharge time (Tphr) and total breath duration (TT) during eupnea. The stimulation of all afferent phrenic fibers lowered the impulse frequency of phrenic motoneurons (f impulses) and shortened both Tphr and TT. When the stimulation was performed during cold block all of the effects on phrenic output persisted, but changes in timing were less pronounced. Under procaine block, only the effects of phrenic nerve stimulation on Tphr persisted. These results suggest that both large and small afferent phrenic fibers control the inspiratory activity with a prominent role of small fibers on phrenic motoneuron impulse frequency.     

Insecticide treated mosquito nets for malaria control in India-experience from a tribal area on operational feasibility and uptake

The study assessed the operational feasibility and acceptability of insecticide-treated mosquito nets (ITNs) in one Primary Health Centre (PHC) in a falciparum malaria endemic district in the state of Orissa, India, where 74% of the people are tribes and DDT indoor residual spraying had been withdrawn and ITNs introduced by the National Vector Borne Disease Control Programme. To a population of 63,920, 24,442 ITNs were distributed free of charge through 101 treatment centers during July-August 2002. Interview of 1,130, 1,012 and 126 respondents showed that the net use rates were 80%, 74% and 55% in the cold, rainy and summer seasons, respectively. Since using ITNs, 74.5-76.6% of the respondents observed reduction of mosquito bites and 7.2-32.1% reduction of malaria incidence; 37% expressed willingness to buy ITNs if the cost was lower and they were affordable. Up to ten months post-treatment, almost 100% mortality of vector mosquitoes was recorded on unwashed and washed nets (once or twice). Health workers re-treated the nets at the treatment centers eight months after distribution on a cost-recovery basis. The coverage reported by the PHC was only 4.2%, mainly because of unwillingness of the people to pay for re-treatment and to go to the treatment centers from their villages. When the re-treatment was continued at the villages involving personnel from several departments, the coverage improved to about 90%.Interview of 126 respondents showed that among those who got their nets re-treated, 81.4% paid cash for the re-treatment and the remainder were reluctant to pay. Majority of those who paid said that they did so due to the fear that if they did not do so they would lose benefits from other government welfare schemes. The 2nd re-treatment was therefore carried out free of charge nine months after the 1st re-treatment and thus achieved coverage of 70.4%. The study showed community acceptance to use ITNs as they perceived the benefit. Distribution and re-treatment of nets was thus possible through the PHC system, if done free of charge and when personnel from different departments, especially those at village level, were involved.     

The development of malaria parasites in the mosquito midgut

The mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.     

Towards a species-selective acetylcholinesterase inhibitor to control the mosquito vector of malaria, Anopheles gambiae

Anopheles gambiae is the major mosquito vector of malaria in sub-Saharan Africa. At present, insecticide-treated nets (ITNs) impregnated with pyrethroid insecticides are widely used in malaria-endemic regions to reduce infection; however the emergence of pyrethroid-resistant mosquitoes has significantly reduced the effectiveness of the pyrethroid ITNs. An acetylcholinesterase (AChE) inhibitor that is potent for An. gambiae but weakly potent for the human enzyme could potentially be safely deployed on a new class of ITNs. In this paper we provide a preliminary pharmacological characterization of An. gambiae AChE, discuss structural features of An. gambiae and human AChE that could lead to selective inhibition, and describe compounds with 130-fold selectivity for inhibition of An. gambiae AChE relative to human AChE.