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Chapter 5, Part 2

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 new and better anti-malarial drugs than those existing before World War II were started on a national scale in 1941 and were greatly expanded after the fall of the Dutch East Indies, the source of 90 percent of the world's quinine in the spring of 1942. During World War II the first phase of investigation conducted under the direction of the Office of Scientific Research and Development and the Board for Coordination of Malarial Studies of the National Research Councilled to the correct use of quinacrine (Atabrine).

When this problem was solved largely as a result of the efforts of Shannon and his group, the second problem, namely, that of finding drugs superior to Atabrine, was attacked. Atabrine administration had a spectacular effect on 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 usefulness of the 4-aminoquinolines and the development of SN-7618, later called chloroquine (or Aralen), which was used most successfully as a suppressive agent in Korea once a week. Over 14,000 drugs were explored in all and about 100 reached the clinical level.

The third phase of World War II investigations was begun in the fall of 1944 or spring of 1945, when it was found that drugs having suppressive effect far greater than Atabrine or quinine still did not cause radical cure, that is, did not prevent relapses in vivax infections. The new orientation began with the re-testing of Plasmochin or pamaquine. Pamaquine, an 8-aminoquinoline, had previously been found to have curative properties by British investigators but had proved too toxic for practical use. Final investigations which led to the demonstration of the clinical usefulness of several analogues of pamaquine-pentaquine in 1946, isopentaquine in 1948 and finally primaquine in 1950-as successively more effective curative anti-malarial agents in vivax infections were first supported by OSRD, then on a smaller scale by the U. S. Public Health Service and finally by the Office of Research and 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 many individuals who participated in these investigations, but it would be unfair to omit mention of Elderfield at Columbia, who synthesized the majority of the 8-aminoquinolines tested, including isopentaquine and primaquine, and Schmidt at Cincinnati, who carried out the essential and difficult task of testing the drugs in animals, including monkeys, before trial on man. All of the curative drugs were first evaluated clinically at Statesville Penitentiary through the cooperation of Army medical officers and medical investigators of the University of Chicago. Clinical studies were later expanded in several Federal prisons by Cooper and Coatney, who with Jones of the University of Pennsylvania later also played a leading role in the evaluation of primaquine in the cure of Korean veterans. It has indeed been a privilege for me to have been associated with this group. The investigations of anti-malarial drugs represent an ideal of cooperative effort seldom obtained in large-scale endeavors.

We will now go back and discuss some of the principles that must be borne in mind in consideration of anti-malarial drugs. Although there are four 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. After this time parasites enter the blood and the trophozoites develop into (1) schizoids, which cause clinical symptoms, and (2) gametocytes, which cause no 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 South Pacific where the troops operated were infected with P. falciparum. Despite this fact, malaria among the troops returning to the United States was confined almost entirely to vivax infections.

At this point it is probably wise to define terms. Suppressive drugs are defined as drugs that act on the blood stages of the disease, the trophozoites. These drugs eliminated the clinical symptoms and in falciparum infections they eliminated the disease. Eventually, the gametocytes are also eliminated because they come from the trophozoites, but the suppressive drugs have no direct effect upon the gametocytes. Prophylactic drugs act on the early tissue stages. The most effective drugs against the tissue stages are the 8-aminoquinolines and the same is true for action against gametocytes. But in falciparum infections, the effect on the tissue stages is of no practical importance because suppressive drugs will terminate the infection.

Vivax malaria has a similar course except for one essential difference-only a fraction of the early tissue stages develop into blood


211

stages during the first attack. The remaining or late tissue stages enter the blood at intervals, and are responsible for the relapses in the vivax infections. (Falciparum malaria is called malignant tertian malaria because it has a high mortality rate, if not treated. Vivax is called benign tertian malaria because it causes relatively few deaths in adults, but it is extremely difficult to cure.) The drugs par excellence for eliminating either early or late tissue stages of vivax malaria and thereby causing radical cure of the disease are the 8-aminoquinolines, of which primaquine is the most effective and the least toxic. It is necessary to understand that 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 be either quinine or chloroquine, together with an 8-aminoquinoline, which preferably is primaquine.

We can dispose with further discussion of falciparum malaria because it offers no major problem in treatment under the regimented conditions in which an army operates. In considering vivax infections there is an important fact that is not generally well known, that is, that there are two types of vivax malaria, the tropical type and the temperate zone type. The tropical type of vivax malaria was met in the Southwest Pacific in World War II and conceivably we could meet it again in the sensitive area of French Indochina. The relapse pattern after infection with a tropical strain of vivax is characterized by a primary attack followed in a few weeks after suppressive treatment is stopped (or after the individual attack is treated with suppressive drugs) by repeated relapses which over a year or two gradually become less frequent. The disease finally terminates spontaneously after several years.

Against this type of malaria we may contrast the temperate zone vivax malaria which is found in this country and, as we now know, in Korea. After injection of sporozoites by mosquitoes a primary clinical attack may or may not occur within a couple of weeks. In about two-thirds of the cases a primary clinical attack will occur if chloroquine suppression is not used in the field. After the early initial attack there occurs a period of long latency (usually about 10 months but it may be as long as a year and a half) followed again by late clinical activity during which frequent relapses occur. Both the St. Elizabeth's strain of malaria that has been studied extensively in this country and the Korean vivax malaria have a natural life span of 2 years. This means that infection during the summer of one year in Korea is followed by a series of relapses the following summer and then the disease dies out.


212

It was known that Korea was a place where malaria could be encountered but strangely enough there was practically no malaria in the United States until May of 1951. At this time rotation began. Malaria reached the very high peak of 629 cases per week in August of 1951. As a result of the emergency situation created by the sudden appearance of a large number of clinical attacks in the United States, a conference on malaria in Korean veterans was called on 3 July 1951. It was decided that other drugs than Atabrine or chloroquine should be tried, if possible, in an attempt to reduce the number of cases of malaria occurring in this country (all the cases were vivax infections). Chloroquine discipline in the Far East Command had in fact been fairly good and malaria was not a very serious problem in the field. But about 10,000 cases eventually occurred in the United States in the summer of 1951. At the time that the emergency meeting was called several curative anti-malarial drugs had been developed: the old German drug pamaquine, isopentaquine (a better drug) and primaquine. The latter two drugs had only been tested in laboratory infections, so to speak, in volunteers at Stateville Penitentiary, but nothing was known about their usefulness in the field.

I think it is of interest to note that these curative compounds differ only in the structure of the terminal group of the side chain. It is also of interest that pamaquine, a curative drug, differs from chloroquine only in that the side chain, which is exactly the same in both drugs, is attached to the 8-position of the quinoline nucleus in pamaquine while in chloroquine the same side chain is attached opposite the nitrogen in the 4-position. Obviously, small changes in chemical structure will change a suppressive drug into one that cures. It would seem that the discovery of primaquine should be easy and obvious, but 35 analogues of pamaquine were tested in humans before primaquine was tested. Primaquine, incidentally, was made by 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 following facts about the curative compounds. It took 90 mg. of pamaquine per day for 14 days to cure the experimental malaria in human volunteers when they were 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, while 240 mg. of isopentaquine turned out to be the maximum tolerated dose in Caucasian subjects. We had the following information on primaquine. It would cure 100 percent of heavily infected individuals at daily doses of 221/2 mg. for 14 days. In light-skinned subjects the maximum tolerated dose of primaquine was 200 or 240 mg., so we had in primaquine a much more effective drug for


213

Caucasians. Gram for gram it was about 4 times or 6 times as effective as pamaquine but it also had a much higher chemotherapeutic index.

Unfortunately, in 10 percent of Negroes or dark-skinned races a serious hemolytic defect occurred. This complication had no relationship to sickle cell anemia. If either pamaquine or primaquine was given daily to sensitive Negroes, it was found that they would develop a severe hemolytic anemia resembling black water fever in about 1 week. However, if this dose of primaquine was reduced to 15 mg. a day, only a transient or slight drop in hemoglobin occurred. In the darker-skinned races, therefore, the factor of safety was much less. It took 90 mg. to cure the heavily seeded experimental infection 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 factor of safety in the Negroes. This was important, because about 10 percent of our troops in Korea were Negroes.

At the time of the meeting in July of 1951, therefore, it was decided that the only chance of controlling malaria in the United States in returning veterans was to use primaquine. Intensive toxicity studies were immediately begun in troops. It was found that 15 mg. of primaquine caused no serious toxicity in tests on about 5,000 troops; about 750 were Negroes and over 4,000 were Caucasian. Studies were also done on natives of mixed Indian and Negro extraction in Nicaragua. Trials in five Army installations and one Marine camp revealed that acute hemolytic anemia did not occur at 10 mg. or at 15 mg. per day; but, in one instance, a moderately severe hemolytic anemia occurred in a Negro who received 20 mg. daily. The other symptoms were nil. In dosages of 15 mg. per day cyanosis due to the development of methemoglobin sometimes occurred. Methemoglobinemia of this degree is not a serious condition but it may alarm the physician. It occurred in 2 percent of patients and about 4 percent had abdominal pain.

The toxicity of primaquine is summarized in table 1. From these data we may conclude that it is not advisable to exceed 30 mg. even in light-skinned Caucasian individuals. Thirty mg. per day will cure all vivax infections that have been encountered to date when combined with a suppressive agent such as chloroquine.

Representative results demonstrating effectiveness of primaquine in treating returning Korean veterans are shown in table 2. The data are from the Army camps, Ft. Knox, Camp Breckenridge, Ft. Meade, Camp Dix, Ft. Benning, and Camp Lejeune. Even 10 mg. of primaquine when administered for 14 days together with chloroquine


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proved highly effective in treating the returning veterans, in that only 21/2 percent relapsed after this daily dose for 14 days. (The relapse rate in 1951 and 1952 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 may occur

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 30 mg. daily.

Table 2. Treatment of Korean Vivax Malaria With Primaquine in 1951 and 1952


Patients

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 are included.

Table 3. Effect of Giving 15 mg. Primaquine Daily for 7 Days Against Korean Vivax Malaria


Patients

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 administered for only 7 days. The regimen now recommended for treating Korean vivax malaria in Army personnel returning from Korea is given in table 4. Chloroquine-total dose 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 chloroquine treatment 15 mg. of primaquine base is given once a day for 14 days.

Table 4. Recommended Curative Treatment During Clinical Attack of Vivax Malaria Acquired in Korea

Day

Chloroquine (base) (grams)

Primaquine (base) (grams)

1st day – initial dose

1st day – 6 hrs. later

0.6


0.3

0.015


None

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 hemoglobin concentration should be determined for any patient whose urine is of extremely dark or brown color.

Another important phase of primaquine investigation was carried out by civilian and military investigators in a cooperative program begun in the summer of 1951. It concerned the development of a program that would cure troops returning to the United States before they came down with malaria in this country. In the summer of 1951, therefore, a mission was sent to the Far East Command for the purpose of determining whether primaquine, which admittedly could produce mild gastrointestinal symptoms in a few individuals in dosages of 15 mg. a day, would increase the incidence of seasickness aboard ship or whether seasickness would enhance the toxicity of primaquine. A large-scale study was done on two returning troop ships. I believe about 2,800 troops were treated with primaquine and another group received placebo. On the USNS Antolak 7 percent of the troops receiving primaquine had seasickness, 61/2 percent receiving placebo had seasickness. No toxicity was noted when 15 gm. daily was given for 14 days during the trans-Pacific voyage. Similar results were obtained on the USNS Marine Phoenix. On the latter ship the voyage was very much more severe, incidence of seasickness was very much higher, but was practically the same in the placebo and primaquine groups. With this information at hand it was, therefore, decided


216

in the fall of 1951 that all troops returning to the United States should receive 14 daily doses of primaquine while aboard MSTS transports on their journey back to this country.

There was no way of following up the patients or the troops that had been treated on the first two ships to get adequate statistics on how effective this regimen would be. A new field experiment was therefore set up in the spring of 1952 before the malaria season began. Volunteers were chosen at random except that all must have been in Korea the summer before and none must have had previous clinical malaria to the best of their knowledge. They were divided into two groups. About 300 were given primaquine for 14 days in April before malaria relapses from infections acquired the summer before were manifest. A little over 300 were given placebo. All men were followed during the next summer. Malaria developed in no individual who had received primaquine during the long latent (winter) interval; 171/2 percent of the troops who received placebo developed malaria. It was then predicted, and correctly so, that if primaquine discipline on ships was effective, malaria in the troops returning to this country might disappear.

The ultimate result of primaquine therapy during the trans-Pacific journey home has been studied in troops returning to the United States from the latter part of October 1951 through August 1953. Approximately the same number of troops returned each month. The troops infected in 1951 had little malaria during the next winter, but during the summer of 1952 a very high peak occurred in troops in this country. Primaquine discipline had officially begun in December 1951, but was poor until August 1952. The troops who developed malaria after August in 1952 were obviously men who had returned earlier and were relapsing because they had not received primaquine on shipboard. The very effective primaquine discipline on MSTS ships carrying troops returning to America since 1952 is reflected by a complete lack of the summer hump of malaria in 1953. The problem, as far as Korean veterans developing malaria in the United States is concerned, is very largely one of discipline on ships returning to this country. The credit for the fine discipline belongs not to civilians, but to the Army medical officers and the 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 present time I believe we would have to use the same type of program used in Korea and it probably would be fairly effective. But malaria in the Southwest Pacific area may be more difficult to cure than the Korean malaria. The Korean malaria is apparently extremely easy to cure, compared to the vivax infections of veterans of World War II.


217

So we still may have a problem in malaria if we should return to the Southwest Pacific. It may not be a very large problem, because under hospital conditions 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 15 mg. of this drug. Yet 30 mg. will cause a severe hemolytic anemia in 10 percent of Negroes and the troops returning probably represent about 30,000 Negroes. An experiment has recently been completed on Negro volunteers known to be susceptible to "primaquine-hemolysis" at Stateville Penitentiary which furnishes at least a partial answer. It was found that after 3 or 4 days a severe hemolytic anemia with very dark urine developed in susceptible individuals receiving 30 mg. of primaquine per day. If the drug was then continued, the hemoglobin returned to normal even when the dose was doubled. In one case the drug was continued for 72 days and after this preliminary period of hemolytic anemia the hemoglobin and red blood count returned to normal range. We know part of the mechanism of this recovery. It appears-and this has been studied by radioactive isotope technics-that when susceptible Negroes develop hemolytic anemia the older red cells are destroyed. 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 that pour out are resistant to the drug. Furthermore, after equilibrium has been reached as the cells age a few are destroyed daily, but the bone marrow continues to make new ones at a rate that prevents development of an anemia. This phenomenon probably explains why it was possible to administer 15 mg. of primaquine, which is so close to the toxic dose in a small percentage of the darker-skinned races, without the development of severe toxicity in a large number of returning troops. It also gives us a great deal of reassurance to know that even though primaquine potentially can produce hemolytic anemia, the hemolytic anemia which may occur after 15 mg. is apt to be mild.

Discussion

Question. I should like to know what the recommended suppressive dose of chloroquine is or what drugs are used at the present time.

Answer. The recommended suppressive dose of chloroquine is 0.5 gm. of chloroquine diphosophate (0.3 gm. of the base) every week. This weekly dose does not cause staining of the skin or appreciable toxicity. It has been a highly successful regimen in Korea and there is no reason to believe that the weekly suppressive dose of 0.3 gm.


218

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 men that I have seen who were infected with malaria, invariably, in their families there 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 implementation of primaquine discipline in the troops returning to the United States should be encouraged to prevent this potential danger.

Answer. At the present time about 95 percent of the troops returning to the United States by ship receive primaquine. Those who are flown back by air, whether they are injured or not, do not receive primaquine, but I believe that they get primaquine after their return to this country in most instances. Prisoners of war who returned to this country were given primaquine after coming here. Although in the past 2 years the possibility of Korean troops infecting civilians has been a real danger, I think with the low incidence of malaria in troops now returning, this danger will be much less. However, eternal vigilance must be maintained.