Parasites: Chemotherapy

CHEMOTHERAPY

The study and management of parasitic disease were seminal to the initiation of the chemotherapeutic era. Amazonian Indians first used quinine-containing extracts of cinchona tree bark to treat malarious patients more than 300 years ago. 

It was in the attempt to synthesize this same antimalarial compound that 19th-century German chemists discovered aniline dyes. The circle closed in the early years of this century when Ehrlich, while investigating the suitability of these dyes as protozoan stains, developed the concept that chemicals might be found that had the capacity to destroy microbial pathogens selectively without damage to the tissues of the human host. Although the most dramatic confirmation of that concept came with the introduction of arsenical compounds for the treatment of syphilis, his first successful chemotherapeutics were directed against protozoan agents. By 1930, chemically synthesized drugs had been marketed for the treatment of malaria, trypanosomiasis, and schistosomiasis.

The introduction and explosive increase in the number and variety of antimicrobic agents introduced in the latter three fourths of the 20th century forever changed the face of medicine. Unfortunately, however, few were effective against parasites because they share the eukaryotic characteristics of their hosts. With the resources of the pharmaceutical companies directed toward the development and introduction of antibacterial agents, work on antiparasitic agents lagged. Because of the lack of safer alternatives, chemotherapeutics synthesized in the preantibiotic era remained critical elements of the parasitologist’s therapeutic armamentarium until very recently. Most required prolonged or parenteral administration, the effectiveness of many was restricted to particular disease stages, and the toxicity of a few mandated that use be limited to very severe or lifethreatening conditions. With time, and at a pace much slower than that seen for the antibacterial agents, newer antiparasitic agents were developed that overcame many of these problems. Their numbers are still limited, and only recently has their safety and efficacy begun to match those of their antibacterial equivalents.

Therapeutic Goals

The process of antiparasitic drug development and use has been shaped to a significantdegree by the concentration of parasitic diseases in the impoverished areas of the world. Community-based public health measures aimed at interrupting pathogen transmission, such as provision of sanitary facilities and clean water supplies, are still often beyond thecapacity of tightly constrained budgets, and the major burden of mitigating the impact of parasitic illnesses in endemic areas often falls on medical auxiliaries or village health workers who, operating in remote and relatively primitive conditions, must examine, di-agnose, and treat sick patients with whom they have only fleeting contact. Given these limitations and the large numbers of the afflicted, optimal therapy requires drugs that are effective in a single dose, easily administered, safe enough to be dispensed with limited medical supervision, and sufficiently inexpensive to be widely used. Few such agents ex-ist. Pharmaceutical companies, faced with the enormous costs of drug development and approval, have been reluctant to expend resources they are unlikely to recover. Until the international community provides the resources needed for the development of more suit-able agents, the full potential of antiparasitic chemotherapy will not be realized.

The practical aspects of antiparasitic therapy are illustrated in the principles govern-ing the treatment of worm infections, which differ significantly from those applied to prokaryotic or protozoan infections. Helminths, with few exceptions, do not multiply within the human host, and severe infections thus require the repeated acquisition of infectious parasites. Interestingly, the intensity of infection or worm burden does not fol-low a normal distribution in human populations. Most infected individuals harbor fewer than a dozen adult worms; a small minority harbor very large worm numbers. Because there is a direct correlation between worm burden and clinical disease, only this minor-ity suffers significant morbidity. Concentrating treatment on those few clinically ill pa-tients moderates the medical impact of a helminthic disease on a community at a cost dramatically lower than that required for mass treatment. Moreover, it is usually unnec-essary to eradicate all worms from treated patients; a significant decrease in the worm burden is adequate to alleviate clinical symptoms. This can often be accomplished with short, subcurative doses that further reduce cost and minimize the likelihood of drug tox-icity. Because this approach can dramatically decrease the total community worm bur-den, the number of worm progeny shed into the environment is similarly reduced and the transmission of the disease slowed or, at times, eliminated.

Structure and Action

With few exceptions, antiparasitic agents have been synthesized de novo rather than developed

from naturally occurring substances. Most are relatively simple and often contain benzene or other ring structures.

It is believed that the majority of antiprotozoan drugs interfere with nucleic acid synthesis or, less commonly, with carbohydrate metabolism. Anthelmintics, on the other hand, apparently act by compromising the worm’s glycolytic pathways or neuromuscular function. In most cases, the parasite and host cells have functionally equivalent target sites. Differential toxicity is achieved by preferential uptake, metabolic alteration of the drug by the parasite, or differences in the susceptibility of functionally equivalent sites in parasite and host.

As has been the case for antibacterial agents, the impact of many antiparasitic agents

has been compromised by the development of resistance in the parasite. This seems to have resulted from mutation and selection in the face of intensive, often prophylactic, drug use. The mechanisms responsible have been studied for only a few parasites, but appear to be related to reduced uptake of drug.