The Problem of Malaria

The search for new antimalarials is of intense current concern, and the contribution of an organometallic approach to the problem is well documented [120]. 

The disease remains the most widespread parasitic pathological condition in the world, with an estimated 1 million deaths per year, the majority children under 5 years of age, 90% inhabitants of sub-Saharan Africa. More than 300 million 

The parasite Plasmodium falciparum, which is responsible for the disease, has proved to be highly adaptable in developing resistance to all of the current range of drugs, such as chloroquine 43 and this resistance is spreading worldwide [121-124]. 

It is clear that these problems of (multiple) resistance are a serious concern. Although the discovery of a new antimalarial that would not eventually succumb to resistance would seem an impossible goal, new strategies based on the chemistry of bioorganometallics have been developed, which may help to hold the line imtil a vaccine becomes available [125]. 

Earlier results obtained with the ferrocifens [81] led Brocard et al. to apply the same concept to the chloroquine series, to produce an analog, ferroquine 45, a ferrocenic structure close to that of chloroquine 43 [132,133]. 

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The use of these artemisinin derivatives in combination with an antimalarial drug with a longer half-life, as recommended by WHO, can not only delay emergence of resistance but also partially overcome the problem of short plasma half-life [19]. Nevertheless, chemically and metabolically more stable artemisinins would bring improvement in malaria therapy and bitherapy (or combination therapy) [20],... 

Hayes (5) has also reviewed the contribution of pesticides to the control of human diseases spread by arthropods and other vectors. Outbreaks of malaria, louse-borne typhus, plague, and urban yellow fever, four of the most important epidemic diseases of history, have been controlled by use of the organochlorine insecticides, especially DDT. In fact, the single most significant benefit from pesticides has been the protection from malaria. Today malaria eradication is an accomplished fact for 619 million people who live in areas once malarious. Where eradication has been achieved it has stood the test of time. An additional 334 million people live in areas where transmission of the parasite is no longer a major problem. Thus, about 1 billion people, or approximately one-fourth of the population of the world, no longer live under the threat of malaria. 

He then turned to the clinical problem of malaria in young children and was scientific team leader at the University of Oxford and Kenyan... 

Malaria illustrates both the possibilities and the drawbacks of infectious disease as a solution to the problems of old age. To our shame, given the lack of real political will to eradicate it, malaria still affects half a billion people every year. The most feared complication, cerebral malaria, is caused by inflammation of the tiny blood vessels in the brain, which leads to fever, convulsions, coma and death in more than a million people each year. As we have seen, inflammation and fever are part of the reaction of the host to infection. If someone dies of cerebral malaria, they die more through the violence of their own immune system s counter-attack than through the virulence of the parasite. 

A variety of factors have contributed to the resurgence of malaria, and continue to foster the disease (47). These include socioeconomic and political problems, as well as inadequacies in public health care. Two principal causes of malarial resurgence were (i) the emergence of insecticide-resistant strains of the anopheline mosquitos which are the vectors for transmission of the disease, and (ii) drug-resistant strains of the parasite responsible for the pathology of the most lethal form of the disease, Plasmodium falciparum. Due to the latter, P. falciparum strains which are resistant to the antimalarial effect of chloroquine are spread throughout most of the areas where the disease is endemic, and resistance to more recently introduced antimalarial... 

To disrupt the endosomal-lysosomal membranes, exogenous agents such as chloroquine, glycerol, fusogenic peptides, and inactivated adenoviruses have often been employed. These agents enhance the efficiency of gene transfer but have some inherent problems. For example, whereas chloroquine has received FDA approval for the treatment of malaria, it is toxic to many cell types in vitro. In high doses, chloroquine may lead to a variety of undesirable side effects in the... 

A previous review of the chemotherapy of malaria [18] surveyed the development of antimalarial drugs up to the end of 1966. The present review is intended to cover advances in our knowledge of the malaria parasite, the testing of antimalarial drugs, the mode of action of known antimalarials, and the possibility of new methods of therapy, in the period, 1966-1970. It will be necessary, however, to describe earlier material in order to provide a complete understanding of the problem. 

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