INTRODUCTION
In its general scientific sense, the term "parasite" includes all of the known infectious agents such as viruses, bacteria, fungi, protozoa, and helminths. In this and the two following chapters, the term is used in a restricted sense to denote the protozoa and helminths. It has been estimated that 3 billion (3 ´ 109) humans suffer from parasitic infections, plus a much greater number of domestic and wild animals. Although these diseases constitute the most widespread human health problem in the world today, they have for various reasons also been the most neglected.
In theory, the parasitic infections should be relatively easy to treat because the etiologic agents are known in almost all cases. Furthermore, recent advances in cell culture techniques have made possible in vitro cultivation of many of the important parasites. These advances have not only laid to rest the traditional view that parasites somehow depend on a living host for their existence but have also enabled us to study parasites by methods similar to those employed in investigations of bacteria, including biochemistry, molecular biology, and immunologic pharmacology. However, many problems remain to be solved before more effective chemotherapeutic agents will be discovered and made available for all of the parasitic diseases.
TARGETS OF CHEMOTHERAPY
A rational approach to antiparasitic chemotherapy requires comparative biochemical and physiologic investigations of host and parasite to discover differences in essential processes that will permit selective inhibition in the parasite and not in the host. One might expect that the parasite would have many deficiencies in its metabolism associated with its parasitic nature. This is true of many parasites¾the oversimplified metabolic pathways are usually indispensable for survival of the parasite and thus represent potential points of vulnerability. However, oversimplified metabolic pathways are not the only opportunity for attack. Although the parasite lives in a metabolically luxurious environment and may become "lazy," the environment is not entirely friendly and the parasite must have defense mechanisms in order to survive¾ie, to defend itself against immunologic attack, proteolytic digestion, etc, by the host. In some instances, necessary nutrients are not supplied to the parasite from the host, although the latter can obtain the same nutrients from the diet. In this situation, the parasite will have acquired the synthetic activity needed for its survival. Finally, the great evolutionary distance between host and parasite has in some cases resulted in sufficient differences among individual enzymes or functional pathways to allow selective inhibition of the parasite. Thus, there can be three major types of targets for chemotherapy of parasitic diseases: (1) unique essential enzymes found only in the parasite; (2) similar enzymes found in both host and parasite but indispensable only for the parasite; and (3) common biochemical functions found in both parasite and host but with different pharmacologic properties. Examples of specific targets and drugs that act on them are summarized in Table 52-1.
ESSENTIAL ENZYMES FOUND ONLY IN PARASITES
These enzymes would appear to be the cleanest targets for chemotherapy. Like enzymes involved in the synthesis of bacterial cell walls (see Chapter 43), inhibition of these enzymes should have no effect on the host. Unfortunately, only a few of these enzymes have been discovered among the parasitic protozoa. Furthermore, their usefulness as chemotherapeutic targets is sometimes limited because of the development of drug resistance.
ENZYMES INDISPENSABLE ONLY IN PARASITES
Because of the many metabolic deficiencies among parasites, there are enzymes whose functions may be essential for the survival of the parasites, but are not indispensable to the host. That is, the host may be able to survive the complete loss of these enzyme functions by achieving the same result through alternative pathways. This discrepancy opens up opportunities for antiparasitic chemotherapy, although insufficiently selective inhibition of parasite enzymes remains an important safety concern.
INDISPENSABLE BIOCHEMICAL FUNCTIONS FOUND IN BOTH PARASITE & HOST BUT WITH DIFFERENT PHARMACOLOGIC PROPERTIES
In the parasite, these functions have differentiated sufficiently to become probable targets for antiparasitic chemotherapy, not because of the parasitic nature of the organism or its unique environment but, more likely, because of the long evolutionary distances separating the parasite and the host. It is thus difficult to discover these targets through studying metabolic deficiency or special nutritional requirements of the parasite. They have usually been found by investigating the modes of action of some well-established antiparasitic agents discovered by screening methods in the past. More recently, comparison of genome databases between the host and the parasite has become practical. The target may not be a single well-defined enzyme but may include transporters, receptors, cellular structural components, or other specific functions essential for survival of the parasite.
DRUGS WHOSE MECHANISMS HAVE NOT YET BEEN CONCLUSIVELY IDENTIFIED
In spite of considerable progress in defining the mechanisms of action of the drugs listed in Table 52-1, there are still wide gaps in our understanding of several other important antiparasitic agents. These include chloroquine and similar antimalarials, diethylcarbamazine, diloxanide, praziquantel, and others. From the biochemical activities that have been identified for them, it appears that many are capable of binding DNA, some can uncouple oxidative phosphorylation, and some inhibit protein synthesis. These types of activity, which are toxic to the host but could also be involved in the antiparasitic action, may have been preferentially detectable in random screenings routinely used for antiparasitic agents in the past.
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