Medical Science Publication No. 4, Volume II
CLINICAL TREATMENT OF MALARIA*
ALF S. ALVING, M.D.
Clinical investigations having as their primary aim the finding of newand better anti-malarial drugs than those existing before World War IIwere started on a national scale in 1941 and were greatly expanded afterthe fall of the Dutch East Indies, the source of 90 percent of the world'squinine in the spring of 1942. During World War II the first phase of investigationconducted under the direction of the Office of Scientific Research andDevelopment and the Board for Coordination of Malarial Studies of the NationalResearch Councilled to the correct use of quinacrine (Atabrine).
When this problem was solved largely as a result of the efforts of Shannonand his group, the second problem, namely, that of finding drugs superiorto Atabrine, was attacked. Atabrine administration had a spectacular effecton the malaria rate in troops during World War II. It is a well known story.The upshot of these investigations was a rediscovery of the usefulnessof the 4-aminoquinolines and the development of SN-7618, later called chloroquine(or Aralen), which was used most successfully as a suppressive agent inKorea once a week. Over 14,000 drugs were explored in all and about 100reached the clinical level.
The third phase of World War II investigations was begun in the fallof 1944 or spring of 1945, when it was found that drugs having suppressiveeffect far greater than Atabrine or quinine still did not cause radicalcure, that is, did not prevent relapses in vivax infections. The new orientationbegan with the re-testing of Plasmochin or pamaquine. Pamaquine, an 8-aminoquinoline,had previously been found to have curative properties by British investigatorsbut had proved too toxic for practical use. Final investigations whichled to the demonstration of the clinical usefulness of several analoguesof pamaquine-pentaquine in 1946, isopentaquine in 1948 and finally primaquinein 1950-as successively more effective curative anti-malarial agents invivax infections were first supported by OSRD, then on a smaller scaleby the U. S. Public Health Service and finally by the Office of Researchand Development, SGO, Department of the Army.
*Presented 28 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington,
D. C.
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It is obviously impossible in the allotted time to give credit to manyindividuals who participated in these investigations, but it would be unfairto omit mention of Elderfield at Columbia, who synthesized the majorityof the 8-aminoquinolines tested, including isopentaquine and primaquine,and Schmidt at Cincinnati, who carried out the essential and difficulttask of testing the drugs in animals, including monkeys, before trial onman. All of the curative drugs were first evaluated clinically at StatesvillePenitentiary through the cooperation of Army medical officers and medicalinvestigators of the University of Chicago. Clinical studies were laterexpanded in several Federal prisons by Cooper and Coatney, who with Jonesof the University of Pennsylvania later also played a leading role in theevaluation of primaquine in the cure of Korean veterans. It has indeedbeen a privilege for me to have been associated with this group. The investigationsof anti-malarial drugs represent an ideal of cooperative effort seldomobtained in large-scale endeavors.
We will now go back and discuss some of the principles that must beborne in mind in consideration of anti-malarial drugs. Although there arefour types of human malaria only two are of importance to the Military.The first of these is falciparum. After sporozoites are inoculated by mosquitoes,tissue stages develop and for 2 weeks the victims do not feel ill. Afterthis time parasites enter the blood and the trophozoites develop into (1)schizoids, which cause clinical symptoms, and (2) gametocytes, which causeno symptoms but serve to re-infect mosquitoes. All of the suppressive drugs-quinine,Atabrine, chloroquine-will wipe out the blood stages of falciparum malaria.Because there are no late tissue stages, the disease is, thereby, cured.During World War II, 50 percent of the natives in the area of the SouthPacific where the troops operated were infected with P. falciparum.Despite this fact, malaria among the troops returning to the United Stateswas confined almost entirely to vivax infections.
At this point it is probably wise to define terms. Suppressive drugsare defined as drugs that act on the blood stages of the disease, the trophozoites.These drugs eliminated the clinical symptoms and in falciparum infectionsthey eliminated the disease. Eventually, the gametocytes are also eliminatedbecause they come from the trophozoites, but the suppressive drugs haveno direct effect upon the gametocytes. Prophylactic drugs act onthe early tissue stages. The most effective drugs against the tissue stagesare the 8-aminoquinolines and the same is true for action against gametocytes.But in falciparum infections, the effect on the tissue stages is of nopractical importance because suppressive drugs will terminate the infection.
Vivax malaria has a similar course except for one essential difference-onlya fraction of the early tissue stages develop into blood
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stages during the first attack. The remaining or late tissue stagesenter the blood at intervals, and are responsible for the relapses in thevivax infections. (Falciparum malaria is called malignant tertian malariabecause it has a high mortality rate, if not treated. Vivax is called benigntertian malaria because it causes relatively few deaths in adults, butit is extremely difficult to cure.) The drugs par excellence for eliminatingeither early or late tissue stages of vivax malaria and thereby causingradical cure of the disease are the 8-aminoquinolines, of which primaquineis the most effective and the least toxic. It is necessary to understandthat there are several actions of anti-malarial drugs: prophylactic, suppressive,gametocyticidal and curative. In curing an acute attack of vivax malaria,it is necessary to give simultaneously a suppressive drug, which can beeither quinine or chloroquine, together with an 8-aminoquinoline, whichpreferably is primaquine.
We can dispose with further discussion of falciparum malaria becauseit offers no major problem in treatment under the regimented conditionsin which an army operates. In considering vivax infections there is animportant fact that is not generally well known, that is, that there aretwo types of vivax malaria, the tropical type and the temperate zone type.The tropical type of vivax malaria was met in the Southwest Pacificin World War II and conceivably we could meet it again in the sensitivearea of French Indochina. The relapse pattern after infection with a tropicalstrain of vivax is characterized by a primary attack followed in a fewweeks after suppressive treatment is stopped (or after the individual attackis treated with suppressive drugs) by repeated relapses which over a yearor two gradually become less frequent. The disease finally terminates spontaneouslyafter several years.
Against this type of malaria we may contrast the temperate zonevivax malaria which is found in this country and, as we now know, in Korea.After injection of sporozoites by mosquitoes a primary clinical attackmay or may not occur within a couple of weeks. In about two-thirds of thecases a primary clinical attack will occur if chloroquine suppression isnot used in the field. After the early initial attack there occurs a periodof long latency (usually about 10 months but it may be as long as a yearand a half) followed again by late clinical activity during which frequentrelapses occur. Both the St. Elizabeth's strain of malaria that has beenstudied extensively in this country and the Korean vivax malaria have anatural life span of 2 years. This means that infection during the summerof one year in Korea is followed by a series of relapses the followingsummer and then the disease dies out.
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It was known that Korea was a place where malaria could be encounteredbut strangely enough there was practically no malaria in the United Statesuntil May of 1951. At this time rotation began. Malaria reached the veryhigh peak of 629 cases per week in August of 1951. As a result of the emergencysituation created by the sudden appearance of a large number of clinicalattacks in the United States, a conference on malaria in Korean veteranswas called on 3 July 1951. It was decided that other drugs than Atabrineor chloroquine should be tried, if possible, in an attempt to reduce thenumber of cases of malaria occurring in this country (all the cases werevivax infections). Chloroquine discipline in the Far East Command had infact been fairly good and malaria was not a very serious problem in thefield. But about 10,000 cases eventually occurred in the United Statesin the summer of 1951. At the time that the emergency meeting was calledseveral curative anti-malarial drugs had been developed: the old Germandrug pamaquine, isopentaquine (a better drug) and primaquine. The lattertwo drugs had only been tested in laboratory infections, so to speak, involunteers at Stateville Penitentiary, but nothing was known about theirusefulness in the field.
I think it is of interest to note that these curative compounds differonly in the structure of the terminal group of the side chain. It is alsoof interest that pamaquine, a curative drug, differs from chloroquine onlyin that the side chain, which is exactly the same in both drugs, is attachedto the 8-position of the quinoline nucleus in pamaquine while in chloroquinethe same side chain is attached opposite the nitrogen in the 4-position.Obviously, small changes in chemical structure will change a suppressivedrug into one that cures. It would seem that the discovery of primaquineshould be easy and obvious, but 35 analogues of pamaquine were tested inhumans before primaquine was tested. Primaquine, incidentally, was madeby Elderfield in 1945 and was first tested in humans at Stateville in 1948.At the time of the conference on malaria in July 1951, we knew the followingfacts about the curative compounds. It took 90 mg. of pamaquine per dayfor 14 days to cure the experimental malaria in human volunteers when theywere infected with the Chesson strain of Southwest Pacific vivax malaria.Isopentaquine was little better; however, it had one advantage over pamaquine.Ninety mg. of pamaquine was the maximum tolerated dose for humans, while240 mg. of isopentaquine turned out to be the maximum tolerated dose inCaucasian subjects. We had the following information on primaquine. Itwould cure 100 percent of heavily infected individuals at daily doses of221/2 mg. for 14 days. In light-skinnedsubjects the maximum tolerated dose of primaquine was 200 or 240 mg., sowe had in primaquine a much more effective drug for
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Caucasians. Gram for gram it was about 4 times or 6 times as effectiveas pamaquine but it also had a much higher chemotherapeutic index.
Unfortunately, in 10 percent of Negroes or dark-skinned races a serioushemolytic defect occurred. This complication had no relationship to sicklecell anemia. If either pamaquine or primaquine was given daily to sensitiveNegroes, it was found that they would develop a severe hemolytic anemiaresembling black water fever in about 1 week. However, if this dose ofprimaquine was reduced to 15 mg. a day, only a transient or slight dropin hemoglobin occurred. In the darker-skinned races, therefore, the factorof safety was much less. It took 90 mg. to cure the heavily seeded experimentalinfection of the Chesson strain of Southwest Pacific malaria with pamaquine,yet 30 mg. was toxic; there was no factor of safety. With isopentaquine,likewise, there was no factor of safety for Negroes. In primaquine we had,therefore, the first drug in which there appeared to be a slight factorof safety in the Negroes. This was important, because about 10 percentof our troops in Korea were Negroes.
At the time of the meeting in July of 1951, therefore, it was decidedthat the only chance of controlling malaria in the United States in returningveterans was to use primaquine. Intensive toxicity studies were immediatelybegun in troops. It was found that 15 mg. of primaquine caused no serioustoxicity in tests on about 5,000 troops; about 750 were Negroes and over4,000 were Caucasian. Studies were also done on natives of mixed Indianand Negro extraction in Nicaragua. Trials in five Army installations andone Marine camp revealed that acute hemolytic anemia did not occur at 10mg. or at 15 mg. per day; but, in one instance, a moderately severe hemolyticanemia occurred in a Negro who received 20 mg. daily. The other symptomswere nil. In dosages of 15 mg. per day cyanosis due to the developmentof methemoglobin sometimes occurred. Methemoglobinemia of this degree isnot a serious condition but it may alarm the physician. It occurred in2 percent of patients and about 4 percent had abdominal pain.
The toxicity of primaquine is summarized in table 1. From these datawe may conclude that it is not advisable to exceed 30 mg. even in light-skinnedCaucasian individuals. Thirty mg. per day will cure all vivax infectionsthat have been encountered to date when combined with a suppressive agentsuch as chloroquine.
Representative results demonstrating effectiveness of primaquine intreating returning Korean veterans are shown in table 2. The data are fromthe Army camps, Ft. Knox, Camp Breckenridge, Ft. Meade, Camp Dix, Ft. Benning,and Camp Lejeune. Even 10 mg. of primaquine when administered for 14 daystogether with chloroquine
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proved highly effective in treating the returning veterans, in thatonly 21/2 percentrelapsed after this daily dose for 14 days. (The relapse rate in 1951 and1952 after chloroquine therapy alone in these same camps was about 45 percent.)These results were indeed a
Table 1. Toxicity of Primaquine
Potential toxicity is the same as that of pamaquine | ||
Toxic effect | Daily dose mg./base at which toxic effect mayoccur | Significance |
Abdominal pain and methemoglobinemia | 20 mg. | Annoying. |
Acute hemolytic anemia | 20-30 mg. | Dangerous (occurs only in Negroes and dark-skinned races). |
Neutropenia | 120-240 mg. | Dangerous. |
Toxicity in Negroes is greater than in other races because:Acute hemolytic anemia occurs in 10 percent of Negroes treated with 30mg. daily.
Table 2. Treatment of Korean Vivax MalariaWith Primaquine in 1951 and 1952
| Drug regimen | ||||
Chloroquine 1.5 gm. (base) in 3 days | Primaquine (base) daily for 14 days | ||||
10 mg.* | 15 mg.* | 20 mg.* | 30 mg.* | ||
Number treated? | 334 | 157 | 182 | 131 | 41 |
Number that relapsed | 146 | 4 | 2 | 0 | 0 |
Relapse rate (percent) | 43.8 | 2.5 | 1 | 0 | 0 |
*Plus chloroquine 1.5 gm. (base) in 3 days.
?Only patients who were followed more than 4 months after treatment areincluded.
Table 3. Effect of Giving 15 mg. PrimaquineDaily for 7 Days Against Korean Vivax Malaria
| Drug regimen | |
Chloroquine 1.5 gm. (base) in 3 days | Primaquine (base) 15 mg./day for 7 days plus chloroquine 1.5 gm. (base) | |
Number treated and followed more than 90 days | 46 | 31 |
Number that relapsed | 23 | 1 |
Relapse rate (percent) | 50 | 3 |
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pleasant surprise. We had an even more pleasant surprise (table 3).Primaquine when given in 15 mg. doses was highly effective when administeredfor only 7 days. The regimen now recommended for treating Korean vivaxmalaria in Army personnel returning from Korea is given in table 4. Chloroquine-totaldose of 1.5 gm. of the base in 3 days (2.5 gm. of chloroquine diphosphate)is given to eliminate symptoms of clinical malaria. Along with chloroquinetreatment 15 mg. of primaquine base is given once a day for 14 days.
Table 4. Recommended Curative Treatment DuringClinical Attack of Vivax Malaria Acquired in Korea
Day | Chloroquine (base) (grams) | Primaquine (base) (grams) |
1st day ? initial dose | 0.6 | 0.015 |
2d and 3d day | 0.3 | 0.015 |
4th to 14th day (inclusive) | None | 0.015 |
Total dose | 1.5 | 0.210 |
Primaquine should be given with meals. The blood hemoglobinconcentration should be determined for any patient whose urine is of extremelydark or brown color.
Another important phase of primaquine investigation was carried outby civilian and military investigators in a cooperative program begun inthe summer of 1951. It concerned the development of a program that wouldcure troops returning to the United States before they came down withmalaria in this country. In the summer of 1951, therefore, a missionwas sent to the Far East Command for the purpose of determining whetherprimaquine, which admittedly could produce mild gastrointestinal symptomsin a few individuals in dosages of 15 mg. a day, would increase the incidenceof seasickness aboard ship or whether seasickness would enhance the toxicityof primaquine. A large-scale study was done on two returning troop ships.I believe about 2,800 troops were treated with primaquine and another groupreceived placebo. On the USNS Antolak 7 percent of the troops receivingprimaquine had seasickness, 61/2percent receiving placebo had seasickness. No toxicity was noted when 15gm. daily was given for 14 days during the trans-Pacific voyage. Similarresults were obtained on the USNS Marine Phoenix. On the lattership the voyage was very much more severe, incidence of seasickness wasvery much higher, but was practically the same in the placebo and primaquinegroups. With this information at hand it was, therefore, decided
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in the fall of 1951 that all troops returning to the United States shouldreceive 14 daily doses of primaquine while aboard MSTS transports on theirjourney back to this country.
There was no way of following up the patients or the troops that hadbeen treated on the first two ships to get adequate statistics on how effectivethis regimen would be. A new field experiment was therefore set up in thespring of 1952 before the malaria season began. Volunteers were chosenat random except that all must have been in Korea the summer before andnone must have had previous clinical malaria to the best of their knowledge.They were divided into two groups. About 300 were given primaquine for14 days in April before malaria relapses from infections acquired the summerbefore were manifest. A little over 300 were given placebo. All men werefollowed during the next summer. Malaria developed in no individual whohad received primaquine during the long latent (winter) interval; 171/2percent of the troops who received placebo developed malaria. It was thenpredicted, and correctly so, that if primaquine discipline on ships waseffective, malaria in the troops returning to this country might disappear.
The ultimate result of primaquine therapy during the trans-Pacific journeyhome has been studied in troops returning to the United States from thelatter part of October 1951 through August 1953. Approximately the samenumber of troops returned each month. The troops infected in 1951 had littlemalaria during the next winter, but during the summer of 1952 a very highpeak occurred in troops in this country. Primaquine discipline had officiallybegun in December 1951, but was poor until August 1952. The troops whodeveloped malaria after August in 1952 were obviously men who had returnedearlier and were relapsing because they had not received primaquine onshipboard. The very effective primaquine discipline on MSTS ships carryingtroops returning to America since 1952 is reflected by a complete lackof the summer hump of malaria in 1953. The problem, as far as Korean veteransdeveloping malaria in the United States is concerned, is very largely oneof discipline on ships returning to this country. The credit for the finediscipline belongs not to civilians, but to the Army medical officers andthe medical officers of MSTS who cooperated in making this program effective.It represents, I think, a very important gain in the therapy of malaria.
What will we do in Indochina if we should ever get there? At the presenttime I believe we would have to use the same type of program used in Koreaand it probably would be fairly effective. But malaria in the SouthwestPacific area may be more difficult to cure than the Korean malaria. TheKorean malaria is apparently extremely easy to cure, compared to the vivaxinfections of veterans of World War II.
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So we still may have a problem in malaria if we should return to theSouthwest Pacific. It may not be a very large problem, because under hospitalconditions 30 mg. of primaquine is safe to use in Negroes. And of course,30 mg. of primaquine is safe to give to white troops.
You may have wondered why there were so few reactions to 15 mg. of primaquine.Less than a dozen cases of hemolytic anemia, none of them very severe,were reported in over 300,000 troops that have now been treated with 15mg. of this drug. Yet 30 mg. will cause a severe hemolytic anemia in 10percent of Negroes and the troops returning probably represent about 30,000Negroes. An experiment has recently been completed on Negro volunteersknown to be susceptible to "primaquine-hemolysis" at StatevillePenitentiary which furnishes at least a partial answer. It was found thatafter 3 or 4 days a severe hemolytic anemia with very dark urine developedin susceptible individuals receiving 30 mg. of primaquine per day. If thedrug was then continued, the hemoglobin returned to normal even when thedose was doubled. In one case the drug was continued for 72 days and afterthis preliminary period of hemolytic anemia the hemoglobin and red bloodcount returned to normal range. We know part of the mechanism of this recovery.It appears-and this has been studied by radioactive isotope technics-thatwhen susceptible Negroes develop hemolytic anemia the older red cells aredestroyed. This leads to an outpouring of new red cells from the bone marrow.The remaining cells which are less than 60 days old and the new cells thatpour out are resistant to the drug. Furthermore, after equilibrium hasbeen reached as the cells age a few are destroyed daily, but the bone marrowcontinues to make new ones at a rate that prevents development of an anemia.This phenomenon probably explains why it was possible to administer 15mg. of primaquine, which is so close to the toxic dose in a small percentageof the darker-skinned races, without the development of severe toxicityin a large number of returning troops. It also gives us a great deal ofreassurance to know that even though primaquine potentially can producehemolytic anemia, the hemolytic anemia which may occur after 15 mg. isapt to be mild.
Discussion
Question. I should like to know what the recommended suppressivedose of chloroquine is or what drugs are used at the present time.
Answer. The recommended suppressive dose of chloroquine is 0.5gm. of chloroquine diphosophate (0.3 gm. of the base) every week. Thisweekly dose does not cause staining of the skin or appreciable toxicity.It has been a highly successful regimen in Korea and there is no reasonto believe that the weekly suppressive dose of 0.3 gm.
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base would not be successful all over the world. As an added assurance,0.6 gm. of chloroquine is well tolerated for long periods of time.
Question. I just want to make a comment. In the cases of menthat I have seen who were infected with malaria, invariably, in their familiesthere was a member of the Armed Forces who came from the Far East Command.I wanted to point this out as a potential danger in our civilian population.It has happened all over the country. I believe that the implementationof primaquine discipline in the troops returning to the United States shouldbe encouraged to prevent this potential danger.
Answer. At the present time about 95 percent of the troops returningto the United States by ship receive primaquine. Those who are flown backby air, whether they are injured or not, do not receive primaquine, butI believe that they get primaquine after their return to this country inmost instances. Prisoners of war who returned to this country were givenprimaquine after coming here. Although in the past 2 years the possibilityof Korean troops infecting civilians has been a real danger, I think withthe low incidence of malaria in troops now returning, this danger willbe much less. However, eternal vigilance must be maintained.
