The Development of Drugs and Diagnosis
“Without quinine, and with no domestic source of atabrine, operations in most of the Far East would be foredoomed to failure. No doubt to the men of the Rising Sun victory seemed almost within grasp”
- Reginald D. Manwell, an American scientist
Drug discovery and diagnosis were critical components of the war, since without atabrine, for example, the Allies may have easily lost the war. The Japanese were aware of this and sought to make malaria their ally when they made the acquisition of the Dutch East Indies one of the first items on their military agenda since it was a region where the majority of the world's quinine was manufactured.
Diagnosis
Malaria diagnosis is dependent on a proper blood examination. The diagnostician must be conversant with all stages of the malaria parasites since a clear diagnosis is obtained only when parasites are found in the blood, which contains more parasites during the high fever period than during the intermittent period. Because asexual parasites are not detectable in the peripheral circulation during estivo-autumnal infection until during the paroxysmal stage, the diagnosis of malaria may be overlooked unless a blood smear is obtained at the appropriate time.
The Army service comprised diagnosis stations. Orderlies were picked from the ranks, some with no prior education, and after six weeks of rigorous instruction, which included having them look at and stain blood films, the army was able to get them precise enough in identifying malarial parasites to be of tremendous value. In the final year of the war in Palestine, the thirty trained individuals were responsible for analyzing 417,000 blood slides.
Figure 27. Thick Blood Flim Method Diagrams
Differential Diagnosis
The differential diagnosis is typically simple, but several illnesses, such as influenza, rheumatic fever, typhoid, para-typhoid fevers, and many others, must be considered. Blood smears from patients in ambiguous comatose states should be carefully examined for malarial parasites since malaria is usually distinguished by the presence of malarial parasites in the blood.
Malaria frequently causes cerebral symptoms as a result of parasite aggregation in the brain, which can result in coma and death. These severe cerebral forms may appear during the winter months and be misdiagnosed as other types of brain disease:
“In the summer the patient may go down with hyperpyrexia, and so the case may be mistaken for heat stroke. I would especially warn against confusing alcoholism with malaria. In a malarious country, a man may be accused of being drunk when he is suffering from malaria.”
- P. H. Manson-Bahr, an English zoologist and physician
Involvement of Birds in Malaria Research
Birds were used extensively for research on malaria because human malaria is not transmissible to any of the lower animals. The only apparent exception is the monkey, which appears to have been developed by one or two investigators after great struggle and failure. As a result, malaria species often seen in lower animals must be used. Monkeys are susceptible to several forms of malaria, and they have been and continue to be extensively employed in this sort of study. Birds, on the other hand, are far less expensive and easy to maintain. For this reason, and since birds are vulnerable to at least 15 types of malaria parasites, they have long been utilized in malaria research.
Figure 28. A Culex mosquito lands near the eye of a bird in Hawaii
Quinine
Quinine was isolated in 1820 from the bark of a cinchona tree endemic to Peru, and Strecker discovered its chemical formula in 1854.
Figure 29. An advertisement for quinine as a malaria treatment from 1927
In terms of medications used to treat malaria, quinine was thought to be the most specific of them, but, as the war proceeded, experts began to doubt its specificity and were forced to revise the fundamental assumptions, leading to the conclusion that quinine is an extremely effective medicine but is undoubtedly selective on some stages of the malaria parasite. However, in terms of medication therapy for the actual attack, quinine remains the gold standard. It is most efficient against benign tertian malaria and has a significant effect on subtertian malaria.
Still, significant dosages of quinine administered to a patient with a large number of subtertian malaria parasites are likely to cause backwater fever due to the abrupt disintegration of the parasites, and the patient may die within twenty-four hours. Headache, ringing in the ears, visual problems, and sweating are all common side effects. Deafness, low blood platelets, and an erratic pulse are among the most serious side effects.
“I never hesitate to give quinine intramuscularly when it is necessary as a remedial measure in severe infections. The results are magical if it is given in the right way and injected deeply into the gluteal muscles”
- P. H. Manson-Bahr
Other Drugs
The following are the lists of malarial drugs other than quinine in chronological order of discovery:
1. Plasmochin
Figure 30. Chemical structure of plasmochin
Dr. Schulemann and his colleagues discovered plasmochin, the first synthetic antimalarial, in 1926 in Germany.
Plasmochin was, however, somewhat disappointing as a treatment for human malaria due to its high toxicity, but the fact that a drug with a highly specific action in malaria could be synthesized suggested that further research could result in new and better antimalarials.
2. Fourneau 710
Figure 31. Proposed biosynthesis of rhodoquinone (Fourneau 710)
Because the Germans did not share the plasmochin composition or production procedure at first, the French, English, Russians, and Italians all deepened their efforts to discover how to create the same medication or to make something better. They were quickly rewarded with "Fourneau 710," a chemical similar to plasmochin.
3. Atabrine
Figure 32. A sign posted at the 363rd Station Hospital in Papua New Guinea during World War II
In the meantime, German scientists were actively engaged in the search for something even better. Their studies culminated in the discovery of atabrine, which was discovered by Mauss and Mietzsch in the laboratories of the I. G. Farbenindustrie-like plasmochin.
Allied troops have obtained extensive expertise in the use of atabrine for malaria suppression. Thousands of men have been given small doses of atabrine on a daily basis for several months to keep the malarial infection from incapacitating them. Without atabrine, it is almost clear that the war with the Axis would have been lost or considerably postponed.
Although atabrine would manage the illness and prevent true malaria sickness as long as it was taken, it would not prevent infection or recurrence later, necessitating more medication development.
4. 612 and DDT
Figure 33. Commercial product concentrate containing 50% DDT
After the United States joined the war, new and more effective methods of treating or preventing malarial infection were discovered. To achieve mosquito control, malaria surveys and control units were arranged, which resulted in a decrease in malaria occurrences and the acquisition of information regarding the epidemiology and species of vector mosquitoes and their behavioral patterns in areas where originally very little was known.
5. Chloroquine
Figure 34. Chemical structure of chloroquine
Although chloroquine frequently fails to prevent relapses in vivax malaria, it is preferable to quinine or atabrine in that it increases the time between relapses. It is also reported to entirely eliminate falciparum malaria. Its antimalarial impact is many times that of atabrine in human instances, as well as in several forms of avian malaria.
Chloroquine has since been thoroughly tested on thousands of cases of malaria (mostly infections acquired in the Mediterranean and Pacific regions) and has been adopted by the US Army Medical Department as an "enhanced malarial therapeutic and suppressive medicine."
6. Paludrine
Figure 35. Chemical structure of paludrine
Paludrine, unlike chloroquine, was created in England by Imperial Chemical Industries.
Paludrine is reported to be as least as effective as atabrine, while it does not turn the skin yellow and is less poisonous. Paludrine, like atabrine, will totally prevent or eliminate falciparum malaria. It will also significantly reduce the amount of vivax (benign tertian) malaria relapses.
7. Pentaquin
Figure 36. The British Medical Journal testing pentaquin along with other drugs
Pentaquin has a substantially stronger capacity to entirely eliminate vivax malaria. It is, however, comparable to plasmochin in that it is too poisonous for ordinary usage.
Pentaquin, like chloroquine, is a result of American research and has undergone extensive testing on birds. When used to treat gallinaceum and lophurae malaria in hens and ducks, it is believed to be 100 times more effective than quinine. Pentaquin may typically eliminate Vivax malaria in two weeks while other medications just provide a symptomatic cure.
Final Words for Malarial Drugs
Despite some remarkable new antimalarials, the quest for the better continues as the ideal malaria-specific drug is yet to be found. There is currently no medicine that is fatal to sporozoites, and hence no drug that can prevent early infection. In addition, no one treatment combines low toxicity with efficacy against all stages of the malaria parasite. No single medicine is both safe and inexpensive enough to be widely used.