ENVIRONMENTAL DISEASE 



yet as that seen in Aedes aegypti) 

 provided signals that difficulties could 

 be anticipated in the application of 

 standardized control procedures in 

 regions where earlier work had been 

 successful. Furthermore, malaria para- 

 sites have emerged markedly resistant 

 to the commonly used antimalarials. 

 This has spurred the search for new 

 antimalarial agents and has indicated 

 the need for extension of more basic 

 parasitologic studies. 



The problem of drug resistance is 

 particularly acute in Southeast Asia. 

 The U.S. Army Research and Devel- 

 opment Command has established a 

 broadly based program of research, 

 largely monitored through the Walter 

 Reed Army Institute for Research, 

 with the collaboration of the U.S. 

 Armed Forces Epidemiological Board 

 and the U.S. Public Health Service. 

 Research efforts have also been inten- 

 sified in a number of other countries. 



The State of Scientific Knowledge 



Further discussion requires subdi- 

 vision into a series of topics, often 

 intricately interassociated. 



Malarial Parasites — Earlier beliefs 

 that malaria was exclusively limited 

 to humans have been modified, since 

 it has been shown that P '.falciparum, 

 P.vivax, and P.malariae can all be 

 passaged to subhuman primates, can 

 establish infections, and that anophe- 

 lines can be infected from such 

 sources and can transmit further to 

 primates. The owl monkey (Aotus 

 trivirgatus) of South America has 

 been particularly useful in these 

 studies, though, unfortunately, it is 

 not readily obtained in large num- 

 bers. Passage of the parasite in such 

 hosts provides material for detailed 

 studies of the host-parasite relation- 

 ship, and is of great value in provid- 

 ing quantities of the parasite for 

 in vitro cultivation and laboratory- 

 controlled studies on parasite metabo- 

 lism, enzyme studies, morphological 

 studies, preparations of antigens, and 

 the like. The importance of extra- 



human cycles for maintenance of the 

 parasites in nature is of obvious in- 

 terest in epidemiology, and awaits 

 critical assessment. 



Detailed morphological studies 

 have provided new insights into the 

 anatomy of the parasite. They prom- 

 ise to provide powerful tools for 

 direct observation of the mechanism 

 of action of antimalarial agents on 

 the parasites. Such studies, coupled 

 with studies of the enzyme systems 

 involved in drug action, should point 

 the way to rational development of 

 antimalarial drugs. These studies are 

 intimately related to studies on the 

 basic structure and biology of the red 

 blood cell. 



There has been a considerable ex- 

 tension of knowledge relating to the 

 exo-erythrocytic cycle of develop- 

 ment of malaria parasites in the ver- 

 tebrate host. This is a particularly 

 important field, since it relates to 

 problems of malaria prophylaxis and 

 to the radical cure of the established 

 infection. Failures in prophylaxis and 

 therapeusis of the non-drug-resistant 

 parasites may be due to failure of the 

 drug to get to the parasite, or the 

 parasite form itself may be less sensi- 

 tive. The former is the likeliest 

 hypothesis. 



The recognition in recent years that 

 strains of P '.falciparum are markedly 

 resistant to 4-aminoquinolines and to 

 widely used antimalarials has pro- 

 duced a spurt of new research. Proj- 

 ects involve the coordinated efforts of 

 synthetic chemists, biochemists, phar- 

 macologists, clinicians seeing drug- 

 resistant cases (particularly in troops), 

 and clinical-laboratory groups study- 

 ing the new drugs and combinations 

 of drugs under controlled conditions. 

 Several different drug combinations 

 are being used to treat drug-resistant 

 cases; in addition to chloroquine, they 

 employ certain sulfones and certain 

 anti-folic acid agents such as amodia- 

 quine and related compounds. The 

 immediate problem, control of the in- 

 fection in the individual, has in large 

 part been met, but there is much 



unresolved in studies of comparative 

 efficacy and in evaluation of the pos- 

 sibility that the parasite will develop 

 resistance to a further range of anti- 

 malarial drugs. 



Intensive search for new antima- 

 larials — not just relatives of known 

 antimalarials — has involved the elab- 

 oration of drug-screening procedures 

 of several types: rodent malaria sys- 

 tems; avian malaria systems; systems 

 monitoring the development of para- 

 sites in mosquitoes or mosquito or- 

 gans, human malaria parasites, using 

 in vitro systems, and, ultimately, ma- 

 laria parasites of humans in humans. 

 Promising leads include phenan- 

 threnes and naphthoquinones, but 

 they are few in relation to the total 

 effort. The "one shot" antimalarial 

 is still a dream. 



Human Host — A prominent ques- 

 tion remains unsolved: What fac- 

 tor(s) cause febrile paroxysm? Newly 

 developed techniques for fractiona- 

 tion of parasites and for fractionation 

 of infected red blood cells may lead 

 to a resolution of this question. 



The sickle-cell trait in humans has 

 been well established as exerting a 

 protective effect in P. falciparum, in- 

 fections. A similar situation has been 

 postulated for the G-6-PD deficiency 

 state, but supporting evidence is not 

 convincing. Further combined field 

 and laboratory studies are indicated. 



The possible relationship of ma- 

 laria to Burkett's lymphome has been 

 advanced on epidemiological grounds; 

 this possibility is currently being 

 studied intensively in East Africa. 



The problem of hemolysis in 

 G-6-PD deficient subjects treated with 

 8-aminoquinolines has been promi- 

 nent in troops in Southeast Asia, 

 and the subject of detailed studies. 

 Other drug-treatment problems have 

 been recognized, particularly the de- 

 velopment of irreversible scotomata 

 following prolonged chloroquine 

 therapy, and agranulocytosis follow- 

 ing diaminodiphenyl-sulfane therapy. 



365 



