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Chapter XVIII

Contents

CHAPTER XVIII

Clinical Trials of Antimalarial Drugs

Harry Most, M.D.

Extensive military operations in various highly malarious regions during the Second World War stimulated intensive research in the chemotherapy of malaria. Interruption of the normal supplies of quinine from the Far East made it necessary, while conserving existing supplies, to reevaluate the efficiency of Atabrine (quinacrine hydrochloride) and other agents with known antimalarial properties and to widen the search for new drugs for the treatment, suppression, and possible cure of malaria.

Numerous investigations were carried out by civilian, military, and public health research groups under contract of the Office of Scientific Research and Development, Committee on Medical Research of the National Research Council, and integrated by the Board for the Coordination of Malarial Studies.1 Approximately 15,000 compounds were studied, and the more promising were given detailed pharmacological and toxicological examination prior to testing in human beings. Important contributions to the knowledge of chemotherapy of malaria resulted from this comprehensive program. Quinacrine proved as good as quinine in most, and superior in some, aspects of treatment. New agents were found that proved superior both to quinacrine and quinine. In addition, other drugs which apparently produce definitive cure of malaria were later found.

The principal purpose of this chapter is to review briefly some of the clinical drug trials made during World War II in relation to their military application in the management of malaria. A note is added on some of these studies as continued, still under the auspices of the U.S. Army, and brought to significant conclusions in the immediate postwar period (p. 594).

PENICILLIN

The occurrence of acute attacks of malaria in military patients who were given large amounts of penicillin for surgical or other infections suggested very early in experience with this antibiotic that it would have no value in the treatment of malaria. Failures to terminate acute attacks with penicillin in amounts of 460,000 to several million units were reported. The im-

1A Joint Body Composed of Representatives of the Office of Scientific Research and Development, the Army, the Navy, the U.S. Public Health Service, and the National Research Council, vols. I-VII. [Official record.]


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pression was further confirmed in the treatment of neurosyphilis with penicillin and in the treatment of fever induced by malarial infection (transmitted by Plasmodium vivax and Plasmodium malariae).2 Of the patients who had remissions of fever, the larger percentage (31 percent of 147 patients) had had no penicillin during therapeutic malaria; the smaller percentage (13 percent of 46 patients) were given 30,000 units every 3 hours for 120 doses, beginning the day after a rise in temperature to 103 F. Again, 15 patients were inoculated with the McCoy strain of P. vivax and studied under various schemes of treatment with penicillin. Each patient received 3 million units.3 This therapy did not reduce the fever, after the cycle of activity, or affect the degree of parasitemia; it did not prevent, postpone, or alter the nature of the attack (chart 26). Penicillin had evidently no place in the prevention, treatment, or suppression of malaria.

HEAVY METALS

Arsenicals-Arsenated benzine compounds (arsphenamine, neoarsphenamine, and oxophenarsine hydrochloride (Mapharsen)) commonly used in the treatment of syphilis have for a long time been known to possess antimalarial properties in varying degrees. Studies made before and during World War II4 showed that they were ineffective against infections caused by P. malariae and P. falciparum. Given intravenously, intramuscularly, or orally, arsenicals were found to possess definite activity in terminating the paroxysms and parasitemia of malaria due to P. vivax, particularly in blood-induced infections; in naturally acquired malaria ascribed to P. vivax, they proved inferior to quinacrine, quinine, and other drugs as regards control of fever, parasitemia, and the interval to relapse. It was found that their intensive use is not without danger, that they offer no practical advantage over more effective drugs, and finally that arsenicals administered alone or in conjunction with quinacrine or bismuth do not affect the natural relapse rate of this disease.

2Personal communication, Maj. Harry H. Gordon, MC, Chief of Communicable Diseases, Harmon General Hospital, Longview, Tex., to the author.
3Hindle, J. A., Rose, A. S., Trevett, L. D., and Prout, C.: The Effect of Penicillin on Inoculation Malaria; A Negative Report. New England J. Med. 232: 133-136, 1 Feb. 1945.
4(1) Werner, H.: Das Ehrlich-Hata Mittel 606 bei Malaria. Deutsche med. Wchnschr. 36 (Pt. 2): 1792-1794, 29 Sept. 1910. (2) Curd, F. H. S.: The Activity of Drugs in the Malaria of Man, Monkeys, and Birds. Ann. Trop. Med. 37: 115-143, September 1943. (3) Goldman, D.: The Use of Mapharsen in the Treatment of Malaria. Am. J.M. Sc. 196: 502-509, October 1938. (4) Morrison, W. H., and Hill, E. R.: Use of Mapharsen in Relapsing Tertian Malaria. [Official record.] (5) Kay, C. F.: Failure of Mapharsen as an Adjuvant to Atabrine in the Treatment of Relapsing Tertian Malaria. J.A.M.A. 127: 984, 14 Apr. 1945. (6) Spector, S., Haviland, J. W., and Coggleshall, L. T.: The Ineffectiveness of Intensive Mapharsen, Bismuth, and Carbarsone as Curative Drugs for Chronic Malaria. Am. J. Trop. Med. 25: 463-467, November 1945. (7) Bispham, William N.: Malaria: Its Diagnosis, Treatment and Prophylaxis. Baltimore: Williams & Wilkins Co., 1944.


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CHART 26.-Penicillin studies in three patients1 with vivax malaria


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Bismuth compounds.-In one study5 reported during World War II, it was shown that prolonged courses of bismuth subsalicylate in conjunction with intensive Mapharsen therapy did not reduce the relapse rate in naturally acquired vivax malaria of Pacific origin. Bismuth compounds have some limited value in therapeutic management through their ability to establish tertian periodicity6 in patients with induced vivax malaria who have daily or irregular paroxysms, by interrupting, although not terminating, the infection.

Antimony compounds-These components have been shown to have antimalarial properties7 both in vivax8 and falciparum9 infections, but practical application was not found for them in the treatment of vivax malaria of Pacific origin. They have been provocative in precipitating clinical attacks of falciparum or vivax malaria in patients under treatment for kala-azar or schistosomiasis. It is of interest, too, that relapses of vivax malaria have occurred in nonendemic areas in patients who had previously received one or more intensive courses of trivalent compounds (stibophen (Fuadin) or tartar emetic) for schistosomiasis japonica, or pentavalent compounds (stibamine glucoside (Neostam) and/or ethylstibamine (Neostibosan)) for kala-azar. The prolonged administration of tartar emetic (30 days or more) in therapeutic amounts (1.8 to 2.25 gm.) in many cases is moderately toxic.

SULFONAMIDES

Shortly after the introduction of the sulfonamides in the chemotherapy of infections, they were found to possess antimalarial activity of varying degree. Although data from many studies10 indicated their limitations, addi-

5See footnote 4 (6), p. 526.
6Young, M. D., McLendon, S. B., and Smarr, R. G.: The Selective Action of Thiobismol on Induced Malaria. J.A.M.A. 122: 492-494, 19 June 1943.
7Schmidt, Hans, and Peter, F. M.: Advances in the Therapeutics of Antimony. Leipzig: Georg Thieme, 1938, pp. 80-82.
8Cole, H. N., DeOreo, G. A., Driver, J. R., Johnson, H. H., and Schwartz, W. F.: Use of Bismuth Injections to Manage Course of Therapeutic Malaria. J.A.M.A. 115: 422-427, 10 Aug. 1940. 
9(1) De Nunno, R.: Azione del tartaro stibiato sui gametociti del plasmodium vivax e del pl. falciparum. Ricerche sperimentali. Riforma med. 54: 1599-1601, 22 Oct. 1938. (2) De Nunno, R.: La stimolazione antimoniale del s.r.e. come mezzo terapeutico mella malaria estivo-autumnale chininoplasmochina-atebrin resistente. Nota preventiva. Riforma med. 51: 1087-1093, 20 July 1935.
10(1) Niven, J. C.: Sulphanilamide (Prontosil) in the Treatment of Malaria. Bull. Inst. M. Research, Federated Malay States (no. 4), pp. 1-27, 1938. (2) Niven, J. C.: Sulphanilamide in the Treatment of Malaria. Tr. Roy. Soc. Trop. Med. & Hyg. 32: 413-418, November 1938. (3) Yamamato, K.: Sulfanilimide in Malaria. Japanese J. Dermat. & Urol. 46: 78, 20 Oct. 1939. (4) Chopra, R. N., Das Gupta, B. M., Sen, B., and Hayter, R. T. M.: Prontosil in Indian Strains of Malaria. Indian M. Gaz. 74: 321-324, June 1939. (5) De Leon, A. D.: El paludismo y su Tratamiento Intra-venoso por las Sulfanilimidas. Medicina, Mexico 20: 551, 10 Nov. 1940. (6) Chopra, R. N., Hayter, R. T. M., and Sen, B.: M. & B. 693 in Indian Strains of Malaria. Indian M. Gaz. 74: 658-660, November 1939. (7) Coggeshall, L. T., Maier, J., and Best, C. A.: Effectiveness of 2 New Types of Chemotherapeutic Agents in Malaria. J.A.M.A. 117: 1077-1081, 27 Sept. 1941. (8) Johnson, C. E., Jr.: Status of Sulfonamide Therapy in Malaria. Am. J.M. Sc. 206: 327-336, September 1943. (9) Schwartz, L., Furst, W., and Flippin, H. F.: Sulfathiazole as an Antimalarial. Am. J. Hyg. Sect. C 34: 160-162, November 1941.


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tional trials were undertaken to determine their suppressive and clinical value in malaria of war origin. Observations showed quite definitely that sulfonamides do not affect the relapse rate of vivax malaria, and successful termination of acute attacks was achieved only with large doses, which not infrequently resulted in sulfonamide toxicity. Fever and parasitemia were not controlled promptly, and relapses occurred early following treatment. In short, sulfonamides were inferior to quinine or quinacrine in terminating acute attacks. They were found to be more effective in malaria caused by P. falciparum. In a study from West Africa, four out of six sulfonamide compounds exerted a definite effect on fever and parasitemia, but all of them were considered inferior to quinine and quinacrine in the treatment of falciparum infections.

It was observed that sufonamides used in the treatment of bacterial infections may suppress parasitemia due to P. falciparum or P. vivax and so delay the diagnosis of malaria in patients currently or recently under treatment for pneumonia or other infections.11

Field studies were conducted in various theaters. It had previously been shown that plasma levels of 4 mg. percent or higher maintained for 28 days after the inoculation of trophozoites of P. falciparum prevented the subsequent development of this infection but failed to suppress experimentally induced infections with P. vivax. In a series of brilliantly conceived and executed experiments by Australian research teams on the chemotherapeutic, suppressive, and prophylactic activity of various drugs, it was demonstrated that daily doses of 1 gm. of sulfamerazine, sulfadiazine, or sulfamethazine would effectively suppress falciparum malaria but would prove ineffective against infections with P. vivax.12

The practical application of sulfamerazine as a suppressive agent in various field studies is summarized in table 73. These observations show that sulfamerazine in daily doses of 0.5 gm. was not a causal prophylactic, that cyanosis and other manifestations of toxicity were not uncommon, that more clinical attacks occurred during suppression with sulfamerazine than with quinacrine and that they occurred sooner after discontinuance of the drug, and that sulfamerazine exhibited a high degree of suppressive activity but was inferior to 0.6 gm. quinacrine weekly.

Thus, the sulfonamides at most have only limited if any value in the practical treatment or suppression of malaria during war or in civilian life if quinine, quinacrine, or equally effective agents are available.

11Page, S. G., Jr., and McCall, J. V., Jr.: Delay in Diagnosing Malaria After Sulfadiazine Therapy; Two Case Reports. South. M.J. 39 : 728-731, September 1946.
12Fairley, N. H.: Chemotherapeutic Suppression and Prophylaxis in Malaria; An Experimental Investigation Undertaken by Medical Research Teams in Australia. Tr. Roy. Soc. Trop. Med. & Hyg. 38: 311-365, May 1945.


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TABLE 73.-Experimental field tests with sulfamerazine, Atabrine, and sulfapyrazine


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FIGURE 60.-Brig. Gen. James S. Simmons and Col. Arthur Fischer, GSC, inspect cinchona seedlings, November 1943. These are being grown in a cinchona seedling hothouse near Washington, D.C., for shipment to South America to be used in production of quinine for treatment of malaria.

CINCHONA ALKALOIDS

Quinine

With the loss, early in the war, of the main sources of quinine, for centuries the drug of choice in the treatment of malaria, the problem of supply was considered sufficiently critical to warrant restriction of cinchona alkaloids to essential purposes in two War Production Board orders.13 If quinine was to be allocated almost exclusively to the Armed Forces, some substitute would have to be made available for civilian use (fig. 60). It was desirable also to find out exactly how efficient the cinchona alkaloids were in the treatment or suppression of malaria, and whether they would be significantly practical for military use. Discussion in this section will be limited to a few important observations in respect to the relative efficiency of quinine or other cinchona alkaloids in the treatment and suppression of malaria.

13War Production Board, Conservation Orders No. 131, 30 Apr. 1942 and No. M-131-a, 19 June 1942.


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Acute attacks

It had been shown that plasma concentrations of quinine of 4.5 mg. per liter (dosage range 0.12 to 1.8 gm. daily) were effective in suppressing and in terminating acute attacks of vivax malaria. Plasma levels of 5.5 mg. per liter suppressed and terminated acute attacks of falciparum malaria.14 Nevertheless, in a field-type experiment with New Guinea strains, daily doses of 0.6 gm. failed to prevent attacks of falciparum malaria, and 0.3 gm. daily was incapable of preventing vivax attacks. When the latter dose was increased to 0.6 gm., complete suppression was achieved in some cases of infection with P. vivax but not in others. By contrast, daily doses of 0.1 gm. of quinacrine were completely effective in suppressing infections with either agent.

In West Africa, daily suppressive doses of 0.3 gm. quinine were associated with a malaria rate of 651 per 1,000 in a group of 1,180 men, with 4 cases of blackwater fever. In another group of 96 men given 0.3 gm. of quinine daily, 70 developed clinical malaria while on this regimen and 7 more while being transferred to quinacrine. On the other hand, in 752 men on relatively small doses of quinacrine (0.4 gm. weekly), the rate was 450 per 1,000 with only 1 case of blackwater fever. This definite discrepancy in attack rate would doubtless have been larger if they had been given what was subsequently found to be the optimum dosage of quinacrine (0.7 gm. weekly).

Relapses

Clinical studies in this country were undertaken15 to determine the effectiveness of maximum doses of quinine in terminating acute attacks of relapsing vivax malaria of Pacific origin. The following results were reported in a comparative study of a group of 100 patients treated with 28.35 gm. of quinine during 14 days and a control group of 150 patients treated with 2.8 gm. of quinacrine during 7 days: The mean level of quinine in the plasma during treatment was 7.3 mg. per liter, well above the demonstrated effective range. Both groups had blood-smear examinations twice weekly after completion of treatment and were observed for 120 days for clinical or parasitemic relapse.

Special considerations

Control of parasitemia-As shown in chart 27, quinacrine proved significantly superior to quinine in rapidly clearing the blood of malarial parasites, in some patients within 12 hours of the first dose. At 24 hours, 26

14Bi-Monthly Progress Report No. 12, Committee on Medical Research, Office of Scientific Research and Development, 1 Sept. 1943, subject: Malarial Chemotherapy, Contract No. OEMcmr-112. 
15(1) Most, H., and Hayman, J. M., Jr.: Relative Efficiency of Quinacrine (Atabrine) and Quinine in Treatment of Acute Attacks of Vivax Malaria. Am. J.M. Sc. 211: 320-324, March 1946. (2) Gordon, H. H., Christianson, H. B., and Lippincott, S. W.: A Comparison of Quinine and Quinacrine in the Treatment of the Clinical Attacks of Vivax Malaria. South. M.J. 39: 631-634, August 1946.


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percent of those treated with quinacrine and only 7 percent of those given quinine were free of parasites, as were 77 percent and 44 percent, respectively, at 48 hours. At 72 hours, only 4 percent of patients treated with quinacrine still showed parasites, and all were clear at 96 hours; almost one-fourth of the patients treated with quinine still had parasitemia at 72 hours, and in a few this persisted as long as 132 hours.

CHART 27.-Rate of disappearance of parasites during treatment of 497 acute attacks of vivax malaria with quinacrine hydrochloride or quinine

Control of fever-The idea frequently advanced that quinine should be used during the first few days of an acute attack because of its superiority in controlling fever quickly was not borne out in this study. Quinine was not significantly more effective in this respect in relapses and was in fact less effective in patients with delayed primary attacks, of whom 32 percent had fever on the second or third day after beginning treatment with quinine, as compared to 16 percent with quinacrine.

Control of other symptoms-It is difficult to evaluate, in relation to therapy, data on such symptoms as headache, backache, nausea, malaise, and weakness, which usually occur in an attack of malaria. Statistically, there was little difference in the duration of these symptoms under treatment with one or the other drug, although clinically one had the impression that such symptoms, particularly weakness and anorexia, were more promptly controlled with quinacrine.


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Toxicity.-Persistent vomiting associated with the malarial attack was controlled by withholding fluids and food by mouth and by giving intravenous glucose prior to the administration of quinacrine. Given several hours of freedom from vomiting, this symptom was not brought on again by the drug.

Gastrointestinal disturbances controlled as described were not aggravated by quinine. Patients with eczematoid or exfoliative dermatitis and malaria had no activation of the skin process attributable to quinine. One patient, who proved to be hypersensitive to the drug, developed acute thrombopenic purpura and severe angioneurotic edema of the face on the first day of treatment. Such reactions, although not unknown, were admittedly rare. A fairly high proportion of patients treated with quinine, however, complained of severe and annoying tinnitus and fullness in the ears or head. In many cases, this seemed to retard full recovery from the symptoms of an acute attack.

No major toxic manifestations were seen during treatment with quinacrine. Patients who alleged previous intolerance to the drug displayed none when it was given to them in colored capsules without their knowledge of the contents. In this series, signs and symptoms referable to the central nervous system were not encountered in relation to quinacrine therapy. Two patients with severe eczematoid dermatitis and acute malaria who were not having specific antimalarial treatment had flareups of the skin process, and many others with the two conditions suffered no ill effects from treatment with quinacrine.

Relapse rate and interval to relapse-Approximately 80 percent of Pacific infections relapsed within the observation period of 120 days, whether treated with quinacrine or quinine, but there was a striking difference in the length of the interval to relapse. In short, the mean interval following treatment with quinine was 22 days as compared with 53 days following treatment with quinacrine (chart 28). Quinacrine thus effected a longer interval to relapse by at least a month, reducing to a minimum the number of relapses occurring within 30 days of treatment and in 30 percent of cases prolonging the interval to more than 60 days.

Falciparum infections

Single intravenous injections of as much as 1.2 gm. of quinine failed to terminate acute attacks caused by P. falciparum in 5 out of 10 patients, while intravenous injection of single doses of 0.4 to 1.0 gm. of quinacrine terminated attacks due to P. falciparum in 49 out of 50 cases at the 20th General Hospital, India-Burma theater. The relative merits of parenteral quinine and quinacrine in fulminating falciparum infections are discussed in the section on quinacrine. Maximum doses of quinine have been shown to produce more minor and major toxic manifestations than therapeutic amounts of quinacrine. Aside from cinchonism, quinine used in 10,000 cases of ma-


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CHART 28.-Relapse rates and intervals to relapse following treatment, by days, with quinacrine hydrochloride or quinine of 250 acute attacks of vivax malaria of Pacific origin

laria was associated with an incidence of purpura in 5 percent, with 2 deaths, whereas no case of purpura occurred in 2,500 cases treated with quinacrine in Panama.16 Fatal bullous erythema following 1.95 gm. and severe dermatitis after 15 gm. of oral quinine were reported in two patients in India. In addition, gluteal abscesses from intramuscular quinine and convulsions followed by death during or shortly after intravenous quinine occurred in eight patients.17

Summary of comparative studies

There remained little question, therefore, after consideration of the data presented, that quinine is a relatively inferior drug in the treatment of acute attacks of vivax malaria or in the suppression of infections with P. vivax or P. falciparum in nonimmune military personnel. Its early use in the Pacific combat areas resulted in numerous "breakthroughs" of falciparum and vivax malaria during suppression and in early and repeated relapses of the latter. Fortunately, quinacrine was available in adequate amounts, and its establishment as the standard drug resulted in effective suppression and satisfactory control of clinical attacks.

16Shrager, J., and Kean, B. H.: Purpura as a Complication of Malaria. Am. J.M. Sc. 212: 54-59, July 1946.
17Essential Technical Medical Data, India-Burma Theater, for June 1945.


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Totaquine

Totaquine (containing not less than 7 percent nor more than 12 percent of anhydrous quinine and not less than 70 percent nor more than 80 percent of total anhydrous crystallizable cinchona alkaloids) was studied at several general hospitals in the Zone of Interior and overseas. Relatively large amounts were available and more could be obtained for civilian or military use. The antimalarial qualities of all the cinchona alkaloids it contained, if additive, could result in substantial saving in quinine and other alkaloids.

In a study carried out at Kennedy General Hospital, Memphis, Tenn., in July 1944, totaquine proved as effective as quinine in terminating acute attacks of malaria due to P. vivax of Pacific origin, but it more frequently produced epigastric distress, blurred vision, dizziness, and severe vomiting. Similar findings were reported in a study at Bushnell General Hospital, Brigham City, Utah. In addition to the patients treated for 5 days, 53 were maintained on suppressive doses (0.6 gm. daily) for 55 days. Of these, 13 (about 25 percent) "broke through" with clinical malaria. Of the treated patients, 60 percent relapsed; the average interval to relapse was 34 days after suppressive treatment with totaquine.

At the 31st Station Hospital in New Caledonia, a study of patients in groups of 80 treated with totaquine, quinine, or quinacrine, for relapsing malaria of Pacific origin, again showed not much difference as to control of parasitemia, fever, and other symptoms.18 Again nausea, vomiting, vertigo, and blurred vision were observed with totaquine and in some cases were severe. Relapses began within 1 week after completion of treatment with totaquine or quinine, reaching their peak in 2 weeks, whereas relapses after quinacrine did not begin until 3 weeks after completion of treatment and reached their peak at 6 weeks. Similar findings were reported from two Army hospitals in another theater.

In summary, these studies indicate that totaquine is as efficient as quinine in terminating acute attacks of malaria, but is more toxic. Moreover, like quinine, totaquine is less effective than quinacrine in controlling fever and parasitemia and in shortening the intervals between relapses.

These factors, in addition to its being inefficient as a suppressive, variable in alkaloid content, and difficult to standardize, would preclude the use of totaquine on a wide scale for military purposes. It could, however, have a useful role in the treatment of malaria in highly immune individuals in whom small amounts of any antimalarial agent are effective in terminating periods of clinical activity. A considerable advantage in the use of totaquine in areas where it is locally available would be the relatively low cost and ease of preparation, permitting the use of low grade barks of poor quinine content.

18Green, R. A.: Totaquine in the Treatment of Malaria. Bull. U.S. Army M. Dept. No. 84, pp. 51-57, January 1945.


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Other Cinchona Alkaloids

Dihydroquinine, more commonly known as hydroquinine, offered an interesting possibility because it not only could be totally synthesized but could be obtained in 95 to 100 percent yield from the hydrogenation of quinine. If the higher therapeutic activity of dihydroquinine claimed for it in studies of malaria in birds could be demonstrated in man, a useful substitute for quinine might be available synthetically, or the effective stores of quinine could be increased from 15 to 20 percent by converting the latter to dihydroquinine. However, clinical tests in the Pacific with total daily doses of 0.3 to 1.8 gm. for 6 days in relapsing vivax malaria failed to show any greater therapeutic activity of dihydroquinine over quinine. One patient complained of blurred vision after a total of 0.6 gm., and three other men receiving 0.3 gm. three times daily complained of vertigo (two patients) and weakness in the legs (one patient). Dihydroquinine therefore offered no advantage over quinine.

The antimalarial activity of quinidine, cinchonine, and cinchonidine have been known for a long time, and their ability in terminating clinical attacks of malaria was demonstrated many years ago.19 Quinidine as an antimalarial was not explored extensively because of its potential cardiac toxicity, nor were cinchonine and cinchonidine, individually representing small fractions of the total cinchona alkaloids. Development of chemical methods20 for estimating plasma levels of these alkaloids made it possible to evaluate their relative antimalarial activity in man. It was shown that plasma levels of 0.1 and 0.5 mg. per liter for cinchonine and 2.5 and 3.0 mg. per liter for cinchonidine for clinical control of acute attacks of malaria were effective against vivax and falciparum infections, respectively, and that these levels were attained with daily doses of 2.0 to 3.0 gm. of cinchonine and 1.0 to 3.0 gm. of cinchonidine. The effective levels of quinine are 4.0 mg. for vivax infections and 5.0 mg. for falciparum infections, although some of the latter may not be controlled with levels as high as 10 mg. per liter. Total daily amounts of 1.5 gm. of quinine (0.65 every 8 hours) will provide levels of 7.0 to 12.9 mg. per liter (average 10.3) , which are adequate to control most infections. Although it may appear that cinchonine and cinchonidine are more effective than quinine by virtue of activity at lower plasma levels, it must be recognized that such levels are obtained only with two to four times the amounts of these drugs in comparison with quinine. Consequently, no practical advantage could be derived from the individual use of cinchonine or cinchonidine in the routine termination of attacks of malaria since they would ultimately have to be derived from cinchona itself. No clinical studies with cinchonine or cinchonidine were undertaken in the Army. However, it was concluded

19Nelson, E. E.: Cinchona and Its Alkaloids in the Treatment of Malaria. A Symposium on Human Malaria. (Pub. No. 15.) Washington: American Association for the Advancement of Science, 1941, pp. 255-260.
20Bi-Monthly Progress Report No. 11, Committee on Medical Research, Office of Scientific Research and Development, 2 July 1943, subject: Malarial Chemotherapy, Contract No. OEMcmr-112.


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from civilian studies that they were less toxic than quinine, particularly with respect to symptoms attributable to the special senses, and that these drugs singly or in combination, as in totaquine, should be approximately equivalent to quinine in antimalarial activity.

Summary of Studies

Studies with cinchona alkaloids during the war were therefore of definite practical value. It was demonstrated that totaquine and its component alkaloids were as effective as quinine but more toxic, that the cinchona alkaloids were inferior to quinacrine in both suppression and termination of acute attacks of malaria, and that the loss of quinine was accordingly not a serious military problem. A rational method of assay of antimalarial properties of drugs was developed and the efficiency of the various cinchona alkaloids reevaluated. No conclusive studies on the relative efficiency of parenteral quinine and quinacrine in the treatment of cerebral malaria were reported, and this problem still requires investigation before a final estimate can be made of the role quinine should play in the therapy of malaria.

QUINACRINE HYDROCHLORIDE (ATABRINE)21

The extensive prewar literature dealing with the antimalarial properties and toxicity of quinacrine has been adequately reviewed.22 Following the introduction of this drug in 1931, it became apparent that the originally advocated dosage schedule of 0.1 gm. three times daily for 5 days was in many cases, particularly in severe falciparum infections, inadequate for prompt and effective control of fever, symptoms, and parasitemia. There were numerous revisions in treatment plans, but there was no rational pharmacological basis for defining what dosage and treatment schedules were best for terminating acute attacks or for suppression. The relative efficiency of quinacrine versus quinine had not been established, and it was questionable whether we would be able to produce adequate amounts of effective antimalarial drugs. Numerous studies were conducted in many laboratories and hospitals in the various theaters. It is the purpose of this section to review briefly basic clinical and other observations that established quinacrine as a highly effective and satisfactory antimalarial during the war.

In 1941, American chemists succeeded in completely synthesizing quinacrine. Chemical, pharmacological, and clinical investigations sponsored by the National Research Council established the identity of the German and American drugs and found no appreciable difference between them as regards side reactions. Rumors that the American preparation was not identical with the German drug could be definitely dismissed. Finally, tremendously increased production assured an adequate supply at least for military use at first and later for civilian and lend-lease purposes.

21Formula: 3-Chloro-7-methoxy-9-(1-methyl-4-diethylamino-butylamino) acridine dihydrochloride. 
22See footnote 4 (7), p. 526.


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General Properties

Practical, highly sensitive, and accurate chemical methods for the estimation of quinacrine concentrations in the blood and tissues made it possible to study its physiological disposition in the human body.23 It was shown that:

* * * Atabrine is almost completely absorbed in the gastrointestinal tract and renal excretion accounts for very little of the daily dose. It may be concluded from these facts and the fact that its plasma concentration becomes stabilized after several days of drug administration at constant dosage, that it is disposed of by the body mainly by processes which result in its degradation. It follows, then, that the major factors which will relate drug administration and plasma drug concentration are those which condition the processes of distribution and degradation in the body.

* * * It was found that the concentration of the drug in plasma, erythrocytes, and leukocytes is in the order of 1, to 1, to 100-200.

* * * Studies * * * in experimental animals indicated that the drug may achieve concentrations in the liver and spleen as high as 10,000-20,000 times those currently observed in the plasma. Localization in other tissues was found to be less extensive, but highly significant. An extension of these distribution studies to the human [subject] * * * demonstrated that a major portion of the administered Atabrine is localized in the tissues of the body, leaving little in the plasma to exert a chemotherapeutic effect. It is in consequence of this that unless large initial doses of the drug are given the initial plasma drug concentrations are invariably low. However, the extensive localization, together with the low rates of degradation and renal excretion, lead to a low rate of decline of the plasma Atabrine concentration, and consequently a low rate of loss of the protection conferred by Atabrine, subsequent to the termination of drug administration.

It was apparent that a rational regimen of quinacrine therapy would have to be designed along the commonly accepted principles of chemotherapy; namely, the administration of sufficient drug when the diagnosis of malaria is made, or when exposure to malaria is anticipated, to obtain the desired plasma concentration, followed by the serial administration of small doses to maintain it.

The next step was to determine the plasma levels of quinacrine that would be effective in the prompt control of symptoms, fever, and parasitemia associated with acute attacks of vivax and falciparum infections. Infections with various strains of P. vivax and P. falcparum, transmitted by mosquitoes or introduced by blood, were established in volunteers and paretics, and different amounts of quinacrine in different treatment schedules were used to produce various plasma concentrations. It was found that if quinacrine concentrations of 30 μg. per liter or more were maintained for 4 days in vivax infections there was complete termination of clinical activity and parasitemia. Levels between 10 and 30 μg. per liter produced temporary or partial effects,

23(1) Brodie, B. B., and Udenfriend, S.: The Estimation of Atabrine in Biological Fluids and Tissues. J. Biol. Chem. 151: 299-317, November 1943. (2) Mackie, Thomas T., Hunter, George W., III, and Worth, C. Brooke: Manual of Tropical Medicine. Philadelphia: W. B. Saunders Co., 1945, pp. 675-677. (3) Shannon, J. A., Earle, D. P., Jr., Brodie, B. B., Taggart, J. V., and Berliner, R. W.: The Pharmacological Basis for the Rational Use of Atabrine in the Treatment of Malaria. J. Parmacol. & Exper. Therap. 81: 307-330, August 1944.


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and levels below 10 μg. per liter produced little or no effect when maintained for 4 days. Infections with P. falciparum required approximately 50 μg. per liter maintained for 6 days for termination of clinical activity and parasitemia.

With the treatment schedule for quinacrine commonly used before 1943 (0.1 gm. three times daily for 5 days), very low concentrations in the plasma were achieved during the first 2 or 3 days of therapy because of the extensive localization of the drug in tissues. If such dosage is continued for a period of days, the plasma levels will rise progressively, as more and more drug accumulates in the tissues, until ultimately they reach sufficient height to terminate the attack. The delay in the initial effect of quinacrine in such a dosage schedule had led to the belief that quinacrine therapy should be preceded by a 2- to 3-day course of quinine. Actually, such a course is undesirable because 24 hours or less after the last dose the plasma level of quinine is no longer effective. If parasitemia is still present, as it often is in cases so treated, there will be a reactivation of the disease during the next few days (of treatment with 0.1 gm. quinacrine three times a day) until the plasma quinacrine level in this schedule becomes effective.

If, on the other hand, total doses of 0.8 to 1.0 gm. of quinacrine are given orally during the first 24 hours of therapy, or by a combination of parenteral and oral routes, high effective plasma concentrations are quickly established and easily maintained by the serial administration of 0.1 gm. three times daily for 6 days. These considerations led to the adoption by the U.S. Army of a standard course of quinacrine therapy consisting of 2.8 gm. during 7 days (1.0 gm. the first 24 hours and 0.3 g.m. daily for 6 more days).24

Clinical Use

In acute attacks-Clinical experience in this country and overseas proved conclusively the efficiency of such a regimen in terminating acute attacks of malaria due to P. vivax and P. falciparum. It was found25 that 2.8 gm. of quinacrine administered as recommended in Circular Letter No. 153, Office of the Surgeon General, 19 August 1943, brought about cessation of fever within 24 hours in approximately 90 percent of cases of vivax malaria and in the remainder within 48 to 72 hours; approximately 80 percent of patients had negative smears within 48 hours and almost 100 percent at 96 hours. Relapses after treatment with quinacrine occurred in an average of 53 days, in contrast to 24 days and the many short-term relapses following treatment with quinine. In the treatment of acute attacks, there were no toxic manifestations similar to those induced by prolonged intensive treatment with quinine.

24Circular Letter No. 153, Office of the Surgeon General, U.S. Army, 19 Aug. 1943, subject: The Drug Treatment of Malaria, Suppressive and Clinical.
25See footnote 15, p. 532.


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In 291 patients, plasma levels were determined during and after 412 attacks of vivax malaria acquired in the South Pacific.26 The average daily levels from the second to the eighth days of treatment with quinacrine were 41 to 52 μg. per liter. The average increase in level 2 to 4 hours after a dose of 0.1 gm. on the second to seventh day was 6.8 to 11.3 μg. per liter above the corresponding fasting level. The average level 4 weeks after completion of 2.8 gm. of quinacrine therapy was 8 μg. per liter. It was found that this regimen produced plasma levels of 45 μg. per liter within 24 hours after treatment was begun and that all symptoms and parasitemia were abolished within 72 hours in almost 100 percent of the patients. No correlation was observed between plasma levels and the occurrence or spacing of relapses.

The question arose whether plasma levels would be affected by such factors as jungle climate, fatigue, combat, and diarrhea. It was shown overseas that diarrhea or dysentery did not influence the pattern of the quinacrine plasma levels during therapy. In this country under simulated jungle conditions, and also overseas, it was shown that high temperatures, humidity, and fatigue did not adversely affect the absorption or stabilization of quinacrine in the plasma.

Quinacrine was found to be effective also in the treatment of delayed primary vivax malaria appearing after discontinuance of quinacrine suppression.27 The continued use of this drug does not produce strains of parasites that are resistant to its action. It was noted that fever and sometimes parasitemia were not so promptly controlled in primary attacks as in relapses, although quinacrine was superior to quinine in both types of attack, and the rate of disappearance of parasites from the blood in a relapse was dependent on the degree of initial parasitemia rather than on the plasma level of quinacrine. This observation has no practical importance, however, since most patients are free of fever and symptoms before parasites have disappeared completely from the blood, and regardless of initial parasite density almost all patients have negative smears within 96 hours after the initiation of an adequate schedule of quinacrine therapy.

Attempts to enhance the response to treatment by increasing the initial or the total dose were made in several oversea installations. However, 2.8 gm. in 3 days, or 3.5 to 4.8 gm. in a week, proved no more effective in controlling the acute attack or affecting subsequent relapse rates than the standard schedule of 2.8 gm. in 7 days. In the control of relapses, short courses of treatment (1.2 gm. in 16 hours or 1.4 gm. in 12 to 16 hours) were effective in terminating acute attacks but, if not followed immediately by suppressive doses, might be succeeded by early relapse or in a malarious area by new infection because of the rapid fall of concentration in the plasma below protective levels. One-

26Ellerbrook, L. D., Lippincott, S. W., Cateno, C. F., Gordon, H. H., and Marble, A.: Plasma Quinacrine Concentration in Treatment of Plasmodium Vivax Malaria Acquired in the South Pacific. Arch. Int. Med. 76: 352-357, November-December 1945.
27London, I. M., Kane, C. A., Schroeder, E. F., and Most, H.: The Delayed Primary Attack of Vivax Malaria. New England J. Med. 235: 406-410, 19 Sept. 1946.


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day treatment courses or less have only a slight advantage in insuring the administration of adequate amounts of drug in a short time, and little is gained in reduction of nursing care since patients with acute malaria are usually sick for several days. Moreover, unrecognized or severe falciparum infections may not be controlled with this amount of medication. A false sense of security may cause carelessness in observation of patients.

A short course totaling 2.2 gm. in 3 days (1.0 gm. on the first day, then 0.6 gm. daily for 2 days) was found, in this country, as effective as 2.8 gm. in 7 days in terminating acute attacks of vivax malaria, with a similar spacing of the intervals to relapse. Many patients were symptom free in 3 days, and in some cases the period of hospitalization could be reduced. Relapse of previously treated falciparum infections, rarely seen in this country, would not constitute a hazard in 3-day treatment of vivax relapses here. Total doses in excess of 2.8 gm. or in periods of less than 7 days are not advocated except possibly in fulminating falciparum infections, since nothing is gained by excessive dosage and there is more risk of toxic reactions.

In falciparum infections-The clinical studies discussed thus far have been concerned principally with vivax infections. It has been noted that experimentally induced falciparum infections were effectively controlled with quinacrine plasma levels in the range of 40 to 50 μg. per liter. Plasma levels in that order are quite uniformly attained by initial doses of 1.0 gm. of quinacrine administered during the first day of treatment by the oral or combined oral and parenteral routes. It was to be expected, then, that standard quinacrine treatment would prove effective in the control of the majority of infections with P. falciparum.

In a report from India28 summarizing the treatment of over 5,000 cases of malaria of which more than two-thirds were due to P. falciparum, it was stated that quinacrine was as effective as quinine in terminating them. This is of particular significance since early in that theater's experience the dosage of quinacrine was 0.1 gm. three times a day for 5 to 7 days. Undoubtedly, higher doses on the first day would have produced even more satisfactory results. In fact, 50 patients so treated responded promptly and were afebrile by the third day.

By contrast, patients treated with quinine for the first 2 days had a reactivation of fever on the third day when quinine was discontinued. It was stated that in this study the patients treated with quinacrine remained febrile a little longer than those treated initially with quinine, but the former had considerably less nausea and vomiting and no tinnitus or deafness. Treatment with quinine was associated with the development of blackwater fever in two patients. One patient developed a fatal diffuse bullous erythema after 1.95 gm. of quinine and another developed an extensive dermatitis after 15 gm.

Extensive experience in West Africa and in various Pacific islands where the majority of initial attacks of malaria were due to P. falciparum demonstrated the efficiency of standard quinacrine therapy in terminating uncomplicated attacks. In general, its value in the more severe forms of malaria is attested by the remarkably low death rate from this disease during the war in conjunction with the widespread use of quinacrine. Fulminating cerebral malaria was fortunately not common in most theaters.

28Ware, R. E., Brem, T. R., and Crane, N. F.: Experiences With Malaria in India. [Official record.]


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In India, of over 6,000 cases of malaria in native or foreign troops there were 140 cases of the cerebral form, or an incidence of about 2 percent of falciparum infections.29 The death rate in American troops with cerebral malaria was 5 percent and in Chinese and other personnel, 33 percent. Quinacrine alone was said to have cured several cases. In another report,30 it was stated that 1 death occurred in 8 patients with cerebral malaria treated with quinacrine intramuscularly, and 31 deaths occurred in 61 patients treated with quinine parenterally. In the latter group, eight patients had convulsions and died shortly after intravenous injection of quinine. Of five additional patients treated with a single infusion of quinacrine (0.8 to 1.0 gm.) for cerebral malaria, one died; this patient had also received more than 1.0 gm. of quinine intravenously.31 In the four patients who recovered, parasitemia was controlled within 48 hours. The serum quinacrine levels 24 hours after the infusion was given varied from 100 to 320 μg. per liter. The mortality for cerebral malaria in a series of 146 patients in the Southwest Pacific treated with quinine parenterally was 37 percent and was 21 percent for 19 patients treated with quinacrine.

Parenteral quinacrine treatment thus gave definite evidence of effectiveness in some cases of cerebral malaria. No comparative studies in sufficient numbers were reported on which to base definite conclusions with regard to the relative efficiency of quinacrine and quinine in severe cases with cerebral involvement. The surgeon in the India-Burma theater stated:

My conclusions as to the relative merits of parenteral quinine and Atabrine (in cerebral malaria) are that I am not certain that either possesses a distinct advantage over the other. Atabrine may have a slight advantage in that (1) it is probably less toxic, (2) its effect persists longer, and (3) it can be given intramuscularly. All data we possess indicate that when given in adequate amounts, it is at least as effective as quinine, and may be more effective. Moreover, if a rapid and prolonged effect is desired 0.8 gm. in a slow intravenous drip (over 4 hours) clears the blood of parasites as rapidly as any other method and a parasiticidal concentration remains in the blood for at least 5 days.32

Intramuscular injections of quinacrine were found useful in vivax and falciparum infections with severe vomiting as a means of attaining high plasma levels promptly. For example, single doses of 0.4 gm. given intramuscularly result in levels of 168, 327, 297, 155, 89, 60, 45, 37, and 20 μg. per liter at 5, 15, 30, 60 minutes and 2, 3, 5, 8, and 24 hours, respectively, after injection. Serial injections of 0.2 gm. at intervals of 4 to 8 hours for 24 hours or more can be expected to maintain high effective levels until oral medication can be instituted.

Following a single intramuscular dose of 0.2 gm. of quinacrine, it was shown33 that the number of motile parasites with finely dispersed pigment was reduced and the number of nonmotile parasites with clumped pigment was increased. Three hours after the injection when the plasma level of

29Fitz-Hugh, T., Jr., Pepper, D. S., and Hopkins, H. U. : The Cerebral Form of Malaria. Bull. U.S. Army M. Dept. No. 83, pp. 39-48, December 1944.
30See footnote 17, p. 535.
31Blumgart, Herrman L., and Pike, George M. : History of Internal Medicine in India-Burma Theater. [Official record.]
32See footnote 17, p. 535.
33Trager, W., Bang, F. B., and Hairston, N. G.: Relation of Plasma Level of Atabrine to Morphology and Motility of Plasmodium Vivax. Proc. Soc. Exper. Biol. & Med. 60: 257-258, November 1945.


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quinacrine was falling rapidly the ratio of motile to nonmotile parasites returned to normal, and since the total parasite count did not change it was suggested the parasites had recovered after temporary damage. Similar changes during the first 3 hours after quinine at levels of 6 to 10 mg. per liter were noted. These observations emphasize the necessity for the continued serial administration of antimalarial agents in sufficient amounts and at properly spaced intervals so that adequate levels would be maintained sufficiently long to terminate clinical activity and parasitemia.

The value of single intravenous infusions of quinacrine in falciparum infections was studied at the 20th General Hospital.

Doses of 0.4 gm., 0.6 gm., and 0.8 gm. in 1,000 cc. of fluid were given intravenously to groups of 10 patients on each dosage schedule, and 1.0 gm. in a single infusion was given to each of 20 patients. The acute attack was terminated in all but one patient (given 0.4 gm.) without further treatment. The duration of fever in the various groups was 8 to 64 hours (average 27.2 hours) and smears became negative in from 1 to 3 days (average 2.2 days). Of the 30 patients treated with 0.8 or 1.0 gm., 19 were observed for a month or more after treatment and 4 relapsed within 3 to 5 weeks. Of the 20 patients who received 0.4 or 0.6 gm., 9 were followed for a month or more and 8 of the 9 relapsed within 10 to 23 days after termination of the attack by intravenous quinacrine. Three patients had brief periods of vomiting shortly after the infusion; one patient had a generalized convulsion; a fifth patient developed an acute state of exhilaration and excitement lasting 5 hours. Two patients with moderately severe cerebral malaria treated with 1.0 gm. or quinacrine intravenously responded well, being out of stupor in 18 hours. Twenty control patients treated for acute attacks of falciparum malaria with quinacrine by mouth all responded well although parasitemia and fever persisted in them a little longer than in the groups treated intravenously. In a comparison of the relative efficiency of single intravenous doses of quinine and quinacrine, it was reported that of 10 patients treated for acute falciparum malaria with 1.2 gm. of quinine in an infusion of 1,000 cc., the attack was terminated in only 5. The remainder continued to have high fever for 60 to 132 hours after treatment and required additional therapy. Three relapses occurred in the successfully treated group 6, 9, and 13 days, respectively, after infusion. Three patients who received single doses of 2.0 gm. of quinine in an infusion developed signs and symptoms of shock. It should be pointed out that these doses of quinine (1.2 and 2.0 gm.) are in the toxic range for this drug and are rarely if ever resorted to therapeutically. Further, a comparison of single doses of quinine and quinacrine does not take into account the rapid excretion of quinine. A more practical estimation would have been the serial administration of nontoxic amounts of quinine intravenously.

From these observations, it is apparent that although quinacrine given intravenously effectively terminates attacks of falciparum malaria such a procedure is not without danger and has little advantage over oral treatment in most cases. In cerebral malaria, comparably high effective plasma levels may be reached as quickly by serial intramuscular injections without the dangers inherent in intravenous therapy. Relapses, which occurred at short intervals after single doses of 0.8 or 1.0 gm. of quinacrine injected intravenously, are very common in falciparum infections after 2.8 gm. given in 7 days by mouth. Finally, the prompt response from intravenous quinacrine reported in Chinese patients with a high degree of immunity may not be


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duplicated in nonimmune white American troops. The question of parenteral quinacrine versus quinine therapy remained unsettled.

In suppression-The dosage of quinacrine for suppressive purposes recommended before World War II was based on evidence derived from malaria rates in various parts of the world, populated, for the most part, by immune natives. Daily doses of 0.05 gm. of quinacrine were considered inferior to a daily dose of quinine, but 0.4 gm. of quinacrine weekly in two divided doses was considered more effective than daily doses of quinine in suppressing clinical malaria.34 Although numerous reports indicated varying success in the suppression of malaria with this divided dose of quinacrine, it was not known when we entered the war how effective such a schedule would be in nonimmune troops in highly malarious zones and under combat conditions.

Studies of the course of plasma levels resulting from 0.4 gm. and 0.6 gm. of quinacrine weekly as well as from larger amounts were conducted in England on volunteers, and in the United States on medical students35 and at a military installation. Of 230 white soldiers observed in active training at Fort Knox, Ky., 100 men received 0.4 gm. of quinacrine weekly and another 100 received 0.6 gm. weekly. Thirty volunteers subjected to conditions simulating jungle climate were given 1.2 gm. during the first week and 0.6 gm. weekly for the next 11 weeks. It was shown that, with constant regimens, the plasma concentrations differed widely in individuals but that the group plasma level at any time was a function of the daily dose, the preexisting level, and the interval since the last dose. The group mean level rose progressively for 4 to 8 weeks to reach an equilibrium, which then remained substantially constant. The equilibrium level for the group given 0.4 gm. weekly was 1.2 μg. per liter, and was 17 for the group on 0.6 gm. weekly. It was shown that a hot, humid environment did not influence the group equilibrium level and that suppressive therapy under such environmental conditions did not affect the rate of acclimatization and performance of the men. The time for reaching equilibrium levels could be reduced from 5 to 6 weeks to 1 week by administering high initial doses for a short period (0.2 gm. daily for 5 to 6 successive days). Similar results and conclusions were reported from studies in England and civilian installations in the United States.

It was obvious that such plasma levels would give little or no protection during the first 4 to 6 weeks, or until maximum equilibrium was attained with these doses. Furthermore, marked variations in individual levels meant that the smaller weekly dosage (0.4 mg.) would frequently fail to protect significant numbers of men, especially if occasional doses were omitted. It was clearly necessary to give a large initial or priming dose before or when troops entered malarious zones in order to give immediate protection and

34The Treatment of Malaria; Study of Synthetic Drugs, as Compared With Quinine, in the Therapeutics and Prophylaxis of Malaria. Fourth General Report of the Malaria Commission, League of Nations, Bull. Health Organ. 6: 895, December 1937.
35Minutes, Subcommittee on the Coordination of Malarial Studies, 3 June 1943, National Research Council. Bulletin on Malaria Research, pp. 99-105.


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prevent clinical "breakthroughs." These data were collected during the early months of 1943. Shortly thereafter, these conclusions were translated in terms of the specific recommendations for suppression of malaria contained in Circular Letter No. 153 (p. 540).

In the meantime, numerous reports from overseas had been received which documented the development of the clinical disease in large numbers of troops shortly after their arrival in malarious areas and clearly demonstrated the value of priming doses and the superiority of from 0.6 to 0.7 gm. quinacrine weekly over 0.4 gm. for suppression. Valuable information was obtained on "breakthroughs" during suppression with 0.4 and 0.6 gm. weekly and the relation of such failures to plasma levels and quinacrine discipline. Brief reference to a few field experiences to elucidate some of the factors associated with poor and successful suppression follows.

The Americal Division, which was on New Caledonia from March to October 1942, was moved to Guadalcanal during October, November, and December, where it remained until March 1943.36 The men were forced to live and fight in hypermalarious areas with little to no field control and no mosquito repellent. Quinacrine, 0.4 gm. weekly, was prescribed but the extent of its use was not known. The malaria rates on Guadalcanal were as high as 2,500 per 1,000 per annum. The ratio of falciparum to vivax infections was 3 to 1. Following removal of these troops to the Fiji Islands and mass treatment ending on 10 June 1943, the rates in August and October were still 4,220 and 2,948 per 1,000 per annum, respectively. In September, 613 men were placed on suppressive doses of quinacrine of 0.4 to 0.6 gm. per week. The malaria rate in this group fell from 219 per 1,000 per month to 23. In November, the Division was placed on 0.4 gm. weekly and this dosage was increased to 0.6 gm. on 12 December. The malaria rate fell from 2,948 per 1,000 per annum to 80 and after 2 months' combat in Bougainville the rate in March 1944 was only 97.1. The experience in this division showed that early suppressive doses of 0.4 gm. weekly were inadequate to control malaria in combat although a moderate degree of satisfactory suppression was obtained in a nonmalarious area under fairly good disciplinary conditions. On the other hand, 0.6 gm. of quinacrine proved highly effective both in malarious areas and in regions free from malaria (chart 29). Another example was the 43d Division, which had also been on 0.4 gm. weekly with a high incidence of malaria. Half the division was taken off suppression and had a malaria rate of 2,000 per 1,000 per annum. The other half was placed on 0.6 gm. weekly and their rate fell to 236 per 1,000 per annum. Again, a naval construction battalion of 840 men, on a suppressive regimen of 0.4 gm. weekly, arrived on Guadalcanal on 12 December 1942.37 During the first 5 weeks, 123 men were down with malaria, about 95 percent of which was due to P. falciparum. In the same report it was stated that two combat infantry outfits on 0.4 gm. weekly entered a highly malarious area and within 2 weeks malaria was occurring at the rate of 40 to 60 cases a day, most of them caused by P. falciparum.

Although the great majority of initial infections in the Pacific islands were caused by P. falciparum, subsequent relapses were principally caused by P. vivax. When adequate amounts of quinacrine were used in termination of the attack of falciparum malaria and when suppressive medication of 0.1

36Essential Technical Medical Data, South Pacific Area, for April 1944. 
37Lewis, R. A.: The Suppression of Malaria. [Official record.]


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CHART 29.-Malaria rates in an infantry regiment under various schedules of suppression with quinacrine hydrochloride, by week

gm. daily was continued, falciparum malaria rarely occurred on discontinuance of suppression.

In the Australian studies that have been referred to,38 it was conclusively shown in volunteers infected with P. falciparum (New Guinea strain) transmitted by mosquitoes that, if 0.1 gm. of quinacrine were administered during the period of infection and for 23 days after the last infective bite, clinical malaria did not occur during suppression or after its termination. Actual cure was demonstrated by subinoculation of 200 cc. of blood into other volunteers. If subinoculation was done on the 9th to 11th days after infection, malaria developed in the recipients, indicating that quinacrine was not a causal prophylactic but effected a cure by permanently destroying the erythrocytic parasites after their appearance in the blood. Similar studies in England and in this country with other strains of P. falciparum also demonstrated the curative action of quinacrine suppression in such infections. In the Australian experiments along the same lines with P. vivax, there was shown complete clinical suppression during therapy but no curative effect, for all the volunteers developed vivax malaria at varying intervals after quinacrine was discontinued.

The practical inferences from these observations were that effective plasma equilibrium having been established, quinacrine administered in doses

38See footnote 12, p. 529.


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of 0.1 gm. daily without interruption would effectively suppress both falciparum and vivax malaria and that, if suppression were continued for about 3 weeks in troops leaving the malarious area, falciparum malaria would not develop. Vivax relapses would occur later and could be effectively terminated with quinacrine or delayed indefinitely if necessary by continued suppression. These results were seen in many studies overseas and in this country.

In one experiment, for example, 107 volunteers were taken to a highly malarious area in New Guinea where they were exposed to infection for 44 days. Initial priming doses were followed by 0.1 gm. of quinacrine daily administered 6 days a week during the period of exposure and for 10 days thereafter. No case of malaria developed during the period of suppression, whereas of 44 men who acted as controls and received no medication, 32 developed malaria (in 9 caused by P. falciparum). Subsequent to the discontinuance of suppressive therapy 25 cases of malaria due to P. vivax developed. No case of malaria caused by P. falciparum developed in the group receiving quinacrine either during or after suppressive treatment. This field study showed definitely the value of quinacrine in absolutely preventing clinical malaria due to P. vivax and P. falciparum during adequate suppression and the curative as well as suppressive action of quinacrine in falciparum infections.

In general, the plan of suppression with doses of 0.1 gm. daily was widely used with excellent results. In one oversea area, it was suggested that troops on patrol or in combat may fail to take occasional doses. Studies with single doses of 0.4 or 0.5 gm. twice a week carried out in the field showed that such a schedule would provide adequate protection and insure affective levels all the time.39 This modified plan was not generally adopted but could be used under circumstances precluding regular daily suppressive medication.

By continuing quinacrine therapy for suppression following termination of acute attacks of vivax infections, it was possible to maintain effective fighting strength in combat units highly seeded with malaria. In this country, continued suppression for 3 months or more reduced the number of hospital admissions for relapses without interrupting training or rehabilitation programs. At one hospital in the United States, for example, 79 men treated with 2.8 gm. of quinacrine in 7 days for acute attacks of vivax malaria of Pacific origin were maintained on 0.1 gm. daily for 150 days after termination of the acute attack. No parasitemia or clinical attack occurred during the 5 months of suppression. In a similar sized group, also treated for acute attacks but not subsequently placed on suppressive therapy, 80 percent relapsed during the first 120 days' observation after treatment. The group given effective protection during 5 months by continued therapy was not thereby protected against subsequent relapse, for 82 percent relapsed during the 120-day period of observation after discontinuance of suppression (chart 30).

39Duncan, G. G.: Quinacrine Hydrochloride as a Malaria-Suppressive Agent for Combat Troops. War Med. 8: 305-318, November-December 1945.


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CHART 30.-Distribution of relapses in two groups of patients after treatment for acute attacks of vivax malaria of Pacific origin

The subject of "breakthroughs" or clinical attacks during suppression received attention at many oversea installations. In India, six patients supposedly taking 0.1 gm. of quinacrine a day were admitted to the 20th General Hospital and found to have plasma levels of 6, 7, 8, 12, 12, and 14 μg. per liter, respectively. In every case, it was possible to show that the individual was able to absorb quinacrine normally, the reason for the low levels being failure to take the prescribed dose daily. In the Southwest Pacific, 80 percent of 116 men who had attacks while on suppression were found to have levels of less than 10, whereas only 25 percent of another group of 853 men had similarly low levels. Seventy-five officers having attacks while supposedly taking 0.1 gm. quinacrine daily were found to have low plasma levels and admitted not taking the drug regularly. On the other hand, four men with acute attacks were found to have levels of from 16 to 30 μg. per liter when admitted. It is possible that self-administered medication for beginning symptoms may account for apparently adequate levels in some "breakthroughs." In a division in the Southwest Pacific, the average level for 1,021 men on suppression for a year or more was 13 μg. per liter and varied from an average of 5 in men who "broke through" to an average of over 20 in companies with good discipline.40

40Schaffer, A. J., and Lewis, R. A.: Atabrine Studies in the Field. I. Relation of Serum Atabrine Level to Breakthrough of Previously Contracted Vivax Malaria. Bull. Johns Hopkins Hosp. 78: 265-281, May 1946.


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Toxicity

Effects of prolonged administration

Toxic reactions, principally related to the gastrointestinal tract and nervous system, associated with the ingestion of quinacrine or its parenteral use had been reported before World War II. In an analysis of toxic reactions observed in 49,681 patients to whom quinacrine had been administered before 1941, it was concluded that neurogenic symptoms (headache, mental depression, delirium, psychoses, convulsions) occurred rarely (less than 1 per 1,000) and that gastrointestinal symptoms (nausea, vomiting, diarrhea) were uncommon and of little significance and were frequently related to the concomitant administration of other drugs. More serious reactions were poorly documented and could not be unequivocably related to quinacrine.

Following our entry into the war and the extensive use of quinacrine over prolonged periods for suppression and frequently for termination of acute attacks with larger amounts of drug than were previously used for either purpose, great interest was stimulated in the potential acute or chronic toxic effects of such medication. No attempt will be made in this section to review the voluminous studies made with various experimental animals. Brief reference will be made to observations on the effects of quinacrine not previously reported or to findings that were of significance during World War II.

Liver and kidneys-Studies of hippuric acid synthesis, serum phosphatase, urea clearance, and liver biopsies (10 cases) performed on 101 men who had been on suppression from 8 to 36 months revealed no abnormalities. Similar negative findings resulted from detailed examinations of liver and kidney function of 43 Oxford University undergraduates who took 0.1 gm. of quinacrine daily over a period of 9 to 12 months.

Studies to discover subclinical hepatic damage in white and Negro American troops who had been taking 0.6 gm. quinacrine weekly for 18 to 24 months were done on various groups of 50 men. The icteric index, urinary urobilinogen, sulfobromophthalein excretion, fibrinogen, galactose tolerance, and cephalin-cholesterol flocculation tests failed to detect any evidence of subclinical hepatic dysfunction.41 On the other hand, there were a few reports of varying degrees of liver disease believed related to quinacrine ingestion.

Four cases of hepatic dysfunction (two subclinical and two severe hepatitis, one of which ended fatally) believed related to quinacrine were reported from an oversea theater. An interesting feature in these cases was the association of corneal edema, manifested by blurred vision. In three of the patients corneal edema became less marked after discontinuance of quinacrine and was aggravated by its readministration. Impaired liver function did not become apparent until 3 to 6 months after the initial episode of visual disturbance. The observers of these patients felt that corneal edema and

41Gottfried, S. P., and Levine, A. C.: Liver Function Studies on Soldiers Under Prolonged Atabrine Administration. J. Lab. & Clin. Med. 30: 853-855, October 1945.


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punctate erosions of the surface epithelium were due to quinacrine, that this was a rare manifestation of quinacrine toxicity, and that its occurrence may be followed by liver disease.

In a large series of Chinese patients receiving quinacrine for suppression or treatment of malaria there were 5 with severe hepatitis and exfoliative dermatitis, 3 of whom died of this complication (incidence 1 in 2,000-3,000 Chinese).42 The rash present in each case appeared as early as the 2d day and as late as the 10th day of medication and consisted of a scarlatiniform, maculopapular, dry, scaling eruption beginning on the face and involving the entire body. Conjunctivitis and exfoliation of the tongue were observed. Jaundice, which appeared several days after the rash, was accompanied by a high ("septic") fever, leukocytosis, proteinuria, and bilirubinuria. The liver was large and tender at first but shrank rapidly. Mental clouding was prominent and death followed in coma in the third to fifth week of the disease. At autopsy there was gross and microscopic evidence of severe hepatitis or necrosis of the liver. It was concluded that quinacrine in previously sensitized individuals was responsible for both the hepatitis and the severe dermatitis.

Aplastic anemia-A small number of cases of aplastic anemia with and without atypical lichen planus had been reported from the Pacific area, and this was thought to be possibly ascribable to quinacrine. In an attempt to determine whether prolonged use of quinacrine was responsible for the production of pathological changes in the body, the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C., instructed laboratory officers to furnish data of quinacrine ingestion with all autopsy protocols, regardless of the cause of death. For some time, nothing of significance was observed. Later, it became apparent that aplastic anemia was the cause of death in a disproportionately large number of cases represented by autopsy material sent from the South and Southwest Pacific Areas where an extensive regimen of quinacrine suppression was in force. Fifty-seven cases of aplastic anemia were the basis of a report43 on the possible relation of this disease and quinacrine. The incidence of aplastic anemia per 100,000 men varied little (0.1 to 0.3) from 1942 to 1945 in the continental United States and all foreign theaters, exclusive of the South and Southwest Pacific Areas and the China-Burma-India theater, where it rose from zero in 1942 to a peak of 2.84 per 100,000 during the last 6 months of 1944. Quinacrine was the common drug in at least 47 cases, 9 others being excluded because of the possible role of arsenic, irradiation, or sulfonamides in the production of the aplastic state. In the group treated principally with quinacrine, the drug had been taken for a period of from 1 to 34 months; in the majority, from 4 to 9 months. Large doses were specifically reported in six cases. Four patients had increased the daily dose to 0.2 gm. for a period of from 3 weeks to 8 months; one patient took 20 to 30 tablets during 4 days before onset of symptoms and another was said to have ingested "massive doses" for 3 weeks before he became sick. Hepatitis was present in 10 cases

42Agress, C. M.: Atabrine as a Cause of Fatal Exfoliative Dermatitis and Hepatitis. J.A.M.A. 131: 14-21, 4 May 1946.
43Custer, R. P.: Aplastic Anemia in Soldiers Treated With Atabrine (Quinacrine). Am. J.M. Sc. 212: 211-224, August 1946.


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and the "quinacrine dermatitis complex" in 25. The liver lesions in five cases were indistinguishable from epidemic hepatitis. Cerebral hemorrhage was the immediate cause of death in 10 cases. The bone marrow in all cases was badly depleted of normal hematopoietic elements, often almost totally so without evidence of extramedullary hematopoiesis. Occasionally, the influx of lymphocytes, plasmocytes, and histiocytes attained such proportions that at first glance the fundamental hypoplastic state was not apparent. One man who received 65 transfusions and lived 10 months had extensive secondary fibrosis of the marrow cavity. Clinically, the onset was gradual in most cases, and purpuric manifestations were commonly seen early. In many cases, the red blood cell count could be maintained at fairly good levels by repeated transfusions, but the white cells and platelets remained uniformly depressed. In 20 cases, the "quinacrine dermatitis complex" preceded the anemia. Although this form of possible quinacrine toxicity has proved fatal in the great majority of cases, recovery has been reported.44

Asymptomatic changes in the skin-Changes in the skin and mucous membranes resulting from the prolonged administration of quinacrine were the subject of numerous reports. They varied from asymptomatic pigmentary changes to severe and disabling forms of dermatitis.

The yellow discoloration of the skin associated with quinacrine ingestion was a common finding in the majority of men on prolonged suppression. The intensity of the discoloration, which is not a toxic manifestation of drug ingestion but rather an expression of its deposition in the skin, varied with duration and dosage of suppression, exposure to sunlight, and complexion, being most marked in subjects with dark skin and hair.

Attempts were made to correlate the degree of fluorescence produced by quinacrine in the skin and plasma levels with the use of a dermofluorometer. A high degree of correlation of induced palmar skin fluorescence with mean plasma levels was found in 33 volunteers on 0.2 gm. daily for 1 week and 0.1 gm. daily for 3 weeks. The peak of fluorescence in the skin was reached in 4 to 5 weeks after initial dosage and decreased slowly over a 12-week period after the drug was discontinued. It was believed that this instrument might be useful in the field in determining whether quinacrine suppression discipline was effective.

Quinacrine discoloration of the sclera, as observed in a small number of individuals, was described45 as consisting of yellowish pigmentation, most marked around the limbus in the part of the sclera exposed in the palpebral fissure, and fading toward the fornices. On the other hand, in jaundice, the pigmentation is most marked in the fornices toward the equator of the globe and fading toward the limbus.

Ochronosis-like pigmentation of mucous membranes, skin, and cartilage was described in many individuals on quinacrine suppression. In a dental

44Most, H., and Hayman, J. M., Jr.: Recovery From Severe Hypoplastic Anemia Associated With Atypical Lichen Planus. Bull. U.S. Army M. Dept. 5: 339-342, March 1946.
45Hayman, J. M., Jr.: Atabrine Pigmentation of the Sclera. Bull. U.S. Army M. Dept. No. 82, pp. 120-121, November 1944.


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survey of 1,000 men in the Philippine Islands, 300 showed bluish-purple pigmentation of the hard palate. The color varied from a light blue purple to intense blue black involving from 1 cm. to the entire palate.46 In another report,47 the incidence in 500 men in the Southwest Pacific Area was 31 percent. The majority of the men with pigmentation of the palate had been on quinacrine suppression for at least 7 months. The nature of the pigment based on staining reactions of biopsy sections was considered to be hemosiderin. A detailed study of a small number of patients showed the ochronosislike pigment to be distributed in the skin, hard palate, nail beds, the cartilages of the nose, ears, epiglottis, and trachea, the conjunctivae and corneoscleral limbus. Phenol and alkaptonuria were excluded as causative factors. Surveys at Harmon General Hospital, Longview, Tex., and Moore General Hospital, Swannanoa, N.C., likewise demonstrated an incidence of 15 to 30 percent of asymptomatic pigmentation as described above in patients who had been on prolonged quinacrine suppression overseas.

Atabrine dermatitis complex-More significant changes in the skin were reported from overseas as causing disability and frequently serious prolonged illness. For security reasons and in order to maintain the morale of quinacrine suppression, the data accumulated were not made generally available at first. It was necessary in the beginning to collect information on the incidence of these reactions and to evaluate fully the relation of quinacrine to them. The possibility of substituting another suppressive agent for quinacrine had to be considered if this cutaneous complex proved to be widespread or if unfounded rumors as to its incidence and severity threatened a breakdown in discipline. Fortunately, this did not occur nor was it found that the incidence of the Atabrine dermatitis complex was very great. The following paragraphs from a report entitled "Evaluation of the Untoward Reactions Attributable to Atabrine" prepared by the Medical Consultants Division of the Surgeon General's Office48 summarize the vast amount of clinical and other data collected overseas and in this country:

Medical officers in the Southwest Pacific Area called attention, in the latter part of 1943, to a characteristic cutaneous syndrome which was occurring in soldiers who had been evacuated from New Guinea and adjacent islands. Lt. Col. Charles L. Schmitt, MC, and Maj. (later Lt. Col.) Thomas W. Nisbet, MC, dermatologists stationed with general hospitals in that area, were the first to submit to The Surgeon General official reports in which they described the disease and its probable etiology. Later, similar cases were reported from all other theaters where suppressive atabrine medication was in general use as a control measure for malaria. This syndrome has been observed most frequently in New Guinea and adjacent islands and in Assam and northern Burma; in other areas only small numbers of cases have occurred.

46Summer, S.: An Oral Manifestation of the Use of Atabrine. [Official record.]
47Lippard, V. W., and Kauer, G. L., Jr.: Pigmentation of the Palate and Subungual Tissues Associated With Suppressive Quinacrine Hydrochloride Therapy. Am. J. Trop. Med. 25: 469-471, November 1945.
48Evaluation of the Untoward Reactions Attributable to Atabrine. Bull. U.S. Army M. Dept. 4: 653-659, December 1945.


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This skin disease which has acquired the name atypical lichen planus is characterized by various * * * types of lesions. * * * Almost all patients have both violaceous, hypertrophic lichenoid plaques and some form of cutaneous eczematoid reaction. During the course of the disease, a considerable number of these patients have acute, "explosive" generalized exacerbations, manifested by oozing eczematoid dermatitis having a predilection for the flexors, groins, axillae, extremities, and neck. Such exacerbations resemble exfoliative dermatitis * * * which is as severe as the cases of primary exfoliative dermatitis described below. The seriousness of such a state and the need for expert management of these patients cannot be overemphasized.

Usually the disease is characterized by the onset of localized violaceous or erythematous eczematoid plaques * * * followed by generalization of the lesions with subsequent appearance of the lichenoid plaques and mucous membrane lesions. * * * Any part of the cutaneous surface may be involved, but there is a predilection for the lower legs, forearms, dorsal surface of hands and feet, face, buttocks, lower anterior surface of the neck, genitalia, mucous membranes of the mouth, eyes, and eyelids. Residual effects and lesions which develop later in the course of the disease include: atrophy; hyperpigmentation (melanin) and depigmentation; diffuse follicular accentuation over the upper back, shoulders, and extremities; changes in the nails; moth-eaten, patchy alopecia; and marked disturbance in sweating function.

* * * A characteristic type of eczematoid dermatitis which also has occurred in individuals taking suppressive Atabrine * * * is characterized by bilateral, symmetrical, violaceous-tinged, vesicular, eczematoid and oozing plaques involving the hands, arms, feet, legs, and sometimes other parts of the body. Secondary pyogenic infection is common. The nail bed and skin of the nail folds are usually involved, frequently resulting in exfoliation of the nails without true suppurative paronychia. With experience, on clinical grounds, one can in most cases distinguish between this eruption and other forms of eczematoid dermatitis. Tentatively the term "symmetrical eczematoid dermatitis" has been used * * *.

It does not seem advisable to make a sharp distinction between the so-called atypical lichen planus and the symmetrical eczematoid dermatitis syndrome. From a broad point of view, it seems that all of these patients have either a lichenoid cutaneous reaction or an eczematoid cutaneous reaction or a combination * * *. A small percentage of the total group have lichenoid lesions alone; a larger group have a combination of lichenoid and eczematoid lesions; and a still larger group have eczematoid lesions that are not accompanied by lichenoid lesions.

* * * reports of general Army experience * * * indicate that Atabrine is the essential etiological factor. The mechanisms resulting in the lichenoid reaction and the eczematoid reaction are probably different. For example, it was observed in a carefully controlled series of cases at Moore General Hospital that the time interval preceding exacerbations of eczematoid lesions is much shorter than with the lichenoid lesions. The fact that the incidence has been so very much higher in New Guinea and adjacent islands and in Assam and northern Burma suggests that climatic or geographic factors may play a contributory role in the etiology. There is evidence that various forms of cutaneous trauma may contribute to the onset and localization of the lesions, particularly the eczematoid phase of the eruption. The sequence of events in many cases suggests that individuals taking suppressive Atabrine have a tendency to acquire chronic eczematoid dermatitis on contact with external allergens (such as certain jungle plants and trees) rather than self-limited contact dermatitis which is the usual course * * *. It appears that cutaneous reactions are more frequent in individuals who have been taking Atabrine in dosages above the recommended suppressive amount (0.7 gm. per week). It should be emphasized that the incidence of these cutaneous diseases has been relatively low, even in New Guinea, and, from the military point of view, has not been an important handicap.


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Since available evidence indicates that we are dealing with one complex, it is suggested that it would be best to group these cutaneous reactions attributed to Atabrine under one heading "Atabrine dermatitis complex" and classify the various manifestations as follows: (1) lichenoid dermatitis; (2) lichenoid and eczematoid dermatitis (both including cases heretofore referred to as "atypical lichen planus"); (3) eczematoid dermatitis (including cases heretofore referred to as "symmetrical eczematoid dermatitis"); (4) exfoliative dermatitis secondary to (1), (2), or (3).

The treatment of these conditions depends for the most part on early recognition of the trouble and discontinuation of Atabrine. In many instances, it is difficult to decide whether or not a given case of eczematoid dermatitis is due to Atabrine. It is necessary to study such cases carefully, with careful observation after withdrawal of Atabrine and possibly cautious trial readministration of the drug (do not attempt readministration of Atabrine to a patient who has had exfoliative dermatitis or a severe generalized eczematoid exacerbation). * * * When possible, such patients should be seen by a competent dermatologist, and every effort should be made to rule out other etiological factors. Parenteral administration of penicillin is indicated in patients with secondary pyogenic infection. Local treatment should be bland and nonirritating, and should consist of preparations such as 1: 9,000 potassium permanganate soaks, Burow's solution soaks, 5 percent aqueous solution of tannic acid spray for oozing intertriginous sites, and application of borated cold cream if a grease is indicated. Preparations such as salicylic acid ointment, tincture of iodine, and sulfonamide ointments should not be used. Arsenicals and bismuth have been tried in some cases without affecting the course significantly; they should not be used. Superficial X-ray therapy, if indicated, should be used only under the direction of a competent dermatologist and in small doses (not more than 75 r and not to exceed a total of more than 375 r to 450 r). At least some of these patients have some degree of light sensitivity. Therefore, exposure to sunlight should be avoided and ultraviolet light therapy should not be used. All patients should be studied from the general medical standpoint, including studies of blood, serum proteins, and liver function. Therapeutic agents such as plasma, liver extract, multiple vitamins, and intravenous glucose should be used when indicated.

The prognosis varies from individual to individual. In general it is excellent, especially if the patient is hospitalized early in the course of the disease * * *. The lichenoid lesions involute slowly, but they do not tend to recur; the eczematoid phase of the eruption may involute rapidly, but it tends to recur and is responsible for the prolonged disability which occurs in some cases. In general, recovery is a matter of weeks and months. Residual hyperpigmentation, depigmentation, and atrophy at the sites of lesions become less pronounced as time goes on and the hypohidrosis which occurs in many patients also improves spontaneously. The course is usually prolonged in all cases of exfoliative dermatitis because of frequent exacerbations. It should be noted that these patients have not been followed for a sufficient length of time to make final statements in regard to the prognosis of these cutaneous reactions.

Another major type of cutaneous reaction which has been attributed to Atabrine is primary exfoliative dermatitis, not secondary to the lichenoid-eczematoid syndrome. This is characterized by acute fulminating exfoliative dermatitis, demonstrably associated with true hypersensitivity to Atabrine. It is in every respect similar to exfoliative dermatitis due to other agents such as arsenicals. This type of cutaneous reaction * * * is believed to be associated with Atabrine, much less commonly with quinine. Hypersensitivity of this degree may constitute a dangerous state in either instance.

Acute reactions to short-term administration

The principal toxic rnanifestations from therapeutic amounts of quinacrine usually employed in terminating acute attacks of malaria or from small


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initial doses early in suppression are related mainly to the skin, gastrointestinal tract, and central nervous system.

Skin.-Acute reactions in the skin related to hypersensitivity or reactivation of eczematoid dermatitis following small amounts of quinacrine have been discussed. In addition, urticaria and pruritus have been described as an uncommon toxic manifestation of quinacrine ingestion. In a report49 from India, 12 cases of pruritus and urticaria, particularly of the palms, were described in the course of quinacrine suppression. In 2 patients, symptoms began within 3 days after suppressive medication was started and, in the other 10 patients, within 2 to 3 weeks. The symptoms subsided in three patients while they were still on the drug and in nine within 4 days after the drug was discontinued. Six patients had no recurrence when quinacrine was readministered, and, in the three who had a recurrence, symptoms disappeared with continued medication.

Gastrointestinal tract-Gastrointestinal symptoms (nausea and vomiting) are rarely encountered with quinacrine during therapeutic termination of acute attacks of malaria. Frequently, these symptoms when present are due to malaria rather than to ingestion of the drug. The administration of quinacrine in colored capsules to patients who stated they could not take it because of gastrointestinal symptoms completely forestalled the development of such symptoms.50 Likewise, giving the drug after meals or with sweetened fluids during an attack of malaria reduced the incidence of nausea. Nausea, vomiting, and diarrhea were reported in large numbers of men on initial suppressive doses of 0.2 gm. twice weekly in some series and not at all in others. Symptoms usually disappeared after three or four doses and occurred only infrequently in the 0.1 gm. daily schedule. Psychological factors, field sanitary conditions, and other reasons were held mainly responsible for gastrointestinal symptoms. The consensus was that these reactions were never severe and almost invariably disappeared if the drug was continued.51

Central nervous system-Before World War II, mental disturbances were reported as occurring in approximately 1 to 2 of every 1,000 cases of malaria treated with quinacrine orally or intramuscularly, and various aberrations of the central nervous system attributed to quinacrine were reported in a number of cases during the war.

In 7,604 patients treated with quinacrine in a period of 7 months at an oversea general hospital, 35 cases of toxic psychosis were observed.52 Total doses of 2.1 gm. quinacrine in a week were routine. The greatest number of reactions occurred within 6 days of completion of therapy, although one was observed after only 0.9 gm. had been given and one developed as late as 12 days after therapy. There were two main types of onset. The most frequent

49Essential Technical Medical Data, India-Burma Theater, for August 1945, inclosure 3 thereto. 
50See footnote 15 (1), p. 532.
51The Drug Suppressive Treatment of Malaria. Bull. U.S. Army M. Dept. No. 73, pp. 29-34, February 1944.
52Gaskill, H. S., and Fitz-Hugh, T., Jr.: Toxic Psychoses Following Atabrine. Bull. U.S. Army M. Dept. No. 86, pp. 63-69, March 1945.


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(65 percent) was marked by excitation, hallucinations, and delusions. The other (35 percent) began with retardation, disorientation, and amnesia for recent events together with confabulation. No constant physical or laboratory findings were obtained. The course of the psychosis was benign in most instances. Sixteen patients were subsequently (after 16 to 210 days) retested with quinacrine and only one showed any untoward reaction, consisting of mild excitement which cleared within 24 hours. There was no evidence that the men who developed toxic quinacrine psychoses were unstable psychologically. Two patients who did not recover developed typical schizophrenic reactions. There was no evidence of latent psychosis in the previous behavior of these two patients. Treatment consisted of restraint, sedation, supervision, and nursing care. The authors believed that the psychoses represented a quinacrine sensitivity reaction following which there was an unreactive period.

In another report from overseas,53 28 cases of quinacrine psychosis were observed in the Americal Division. The degree of malarial infection and the great number of relapses treated in this division would indicate the incidence of this reaction to be extremely low. Two patients gave a history of previous psychotic reactions to quinacrine, and in two additional patients it was believed that schizophrenia was induced by the drug. Only one case was noted during the standard course of 2.8 gm. of quinacrine in 7 days. The remainder developed during or after larger total doses, 18 patients receiving more than 3 gm. Confusion was the prominent clinical feature of the psychosis in 27 patients. Hallucinations occurred in eight cases. Recovery was complete within 10 days in 16 patients. By the use of the Koh's block test, these authors showed that there was evidence of confusion in 7 of 31 patients treated with 4.5 gm. quinacrine during 9 days, while no such changes could be demonstrated in 27 patients treated with 2.1 gm. in 7 days. Additional cases of quinacrine psychosis were reported from various installations overseas and in the United States, but their incidence was an insignificant fraction of the total number of psychoses that occurred in the U.S. Army.

Convulsions were reported in six patients treated with "massive" amounts of quinacrine orally54 and in two who were treated intravenously. The convulsions occurred during treatment or on the following day, with unconsciousness for 5 to 15 minutes followed by confusion. Within 24 hours, these patients were all mentally clear. Plasma levels determined in three cases were from 180 to 280 μg. per liter. Studies were stimulated by observation of high plasma levels with parenteral quinacrine therapy and by reports in the literature before World War II55 of mental changes associated with parenteral medication. A group of 13 volunteers were given 0.9 gm. of quinacrine

53Newell, H. W., and Lidz, T.: The Toxicity of Atabrine to the Central Nervous System. I. Toxic Psychoses. Am. J. Psychiat. 102: 805-818, May 1946.
54Newell, H. W., and Lidz, T.: The Toxicity of Atabrine to the Central Nervous System. II. Convulsions. Am. J. Psychiat. 102: 805-818, May 1946.
55See footnote 34, p. 545.


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daily for 7 days. Peak plasma levels were from 156 to 420 with a mean of 286 μg. per liter. No symptoms or signs related to the nervous system were observed. Electroencephalographic studies revealed only small and inconsistent changes not characteristic of those observed in convulsive disorders of the brain. In another study, five normal subjects were given sufficient quinacrine by mouth during 7 to 10 days to produce plasma levels in excess of 100 μg. per liter. In all cases, there was evidence of marked psychologic stimulation (motor acceleration, restlessness, sleeplessness, and increased capacity for work), and the electroencephalogram showed a significant shift toward faster frequencies. These manifestations appeared by the third day and persisted for 6 to 8 days after the drug was discontinued. The authors considered the data convincing evidence that quinacrine acted as a cortical stimulant.

Summary of Studies

An experimental approach to the chemotherapy of malaria led to a rational use of quinacrine for effective treatment of attacks and for suppression. The development of chemical methods for estimating quinacrine in biological fluids and tissues resulted in a better understanding of the limitations of treatment and suppressive schedules in use before and early in World War II. Clinical and field studies carried out on a large scale demonstrated that quinacrine if properly used was superior to totaquine or its component alkaloids for treatment or suppression of malaria due to P. vivax or P. falciparum. Quinacrine produced more prompt control of fever, symptoms, and parasitemia; was less toxic; and provided a longer interval to relapse than quinine, sulfonamides, or heavy metals. Quinacrine was shown to induce definitive cure in falciparum infections and to provide effective suppression of relapsing malaria when priming initial doses were followed by daily doses of 0.1 gm. Failures in suppression (breakthroughs) were shown mainly due to poor discipline and failure to take the drug. Parenteral use of quinacrine was found effective in severe falciparum infections, but no conclusive comparative study was reported between quinine and quinacrine given parenterally. Toxic reactions known before the war were encountered, these consisting of minor gastrointestinal symptoms and toxic psychoses. In addition, prolonged quinacrine ingestion produced edema of the cornea in some cases, and in a large number of cases, the following reactions were described: (1) Ochronosis-like pigmentation of skin, mucous membranes, and cartilage (possibly with hepatitis), (2) urticaria and, more significantly, a dermatitis complex (atypical lichen planus and/or eczematoid dermatitis), and (3) aplastic anemia. It was only shown that long-continued suppression produced these reactions in only a small proportion of men taking the drug and that on the whole no significant disturbances in organ function resulted. The proper use of quinacrine made possible effective military operations in highly malarious areas.


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4-AMINOQUINOLINE COMPOUNDS

The background for the elaboration and study of this group of compounds is reviewed in a report on investigations of potentially antimalarial drugs in the laboratories of the I. G. Farben Werke in Elberfeld, Germany. Following the discovery, in 1924, of Plasmochin (a trade name for pamaquine naphthoate, an 8-aminoquinoline) interest was centered on the possibilities of quinoline derivatives. A total of 314 acridine derivatives were prepared, but none was found to be more active than quinacrine. In 1929, work with the 4-aminoquinoline compounds was begun, and in 1934 a compound as effective as quinacrine was discovered and furnished the impetus for the preparation of numerous derivatives during the years following. Although this information was not available to us during World War II, it is of interest that two reports appeared in the French literature which discussed very generally the antimalarial properties of Sontochin (SN 6,911), one of the 4-aminoquinoline drugs prepared in Germany.

This drug became available in North Africa during the Second World War, and its chemical identity was established. It was subsequently synthesized and made available to the U.S. Army for experimental and clinical testing. A brief discussion of the antimalarial properties of Sontochin is presented, to be followed in turn by brief discussions of several other derivatives prepared in this country, particularly SN 7,618 or Chloroquine Diphosphate, which proved to be the most effective. The proper uses of Plasmochin, rediscovered during the war, will be discussed in due course.

Sontochin (SN 6,911)56

General properties

Absorption of the bisulfate of SN 6,911 is essentially complete whereas only about 80 percent of the binaphthoate is absorbed. Following its absorption, the drug is extensively localized in the tissues. About 25 percent of the daily dose is excreted; about 75 percent is degraded. The plasma level falls approximately 25 percent per day. Daily doses of 0.3 gm. of base result in mean plasma levels of 160 μg. per liter (range 66 to 292). Therapeutic effects in vivax infections, that is, control of fever and parasitemia without recurrence within 14 days, are obtained with mean plasma levels above 80 μg. per liter for 4 days and, in falciparum infections, with levels of 110 to 200 μg. per liter for 6 days. A therapeutic schedule consisting of 0.9 gm. on the first day and 0.3 gm. daily for 3 additional days produces plasma levels of from 125 to 193 μg. per liter for 4 days and is effective in terminating induced vivax and falciparum infections.

56Formula: 3-Methyl-7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline bisulfate or binaphthoate.


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Clinical testing

Acute attacks-The relative efficiency of SN 6,911 and quinacrine in the treatment of acute attacks of vivax malaria of Pacific and Mediterranean origin was studied at Harmon General Hospital. A total of 99 patients were treated with 3.2 gm. of SN 6,911 base during 7 days. There was prompt control of fever and symptoms (86 to 100 percent fever free on the second day), but not significantly more so than with quinacrine, and parasites disappeared from the blood at approximately the same rate with either drug. Of 75 patients followed for at least 60 days after completion of treatment, 49 (about 65 percent) relapsed; the interval to relapse was shorter, 27 percent occurring in the first 5 weeks after treatment with SN 6,911, compared with only 7 percent in the same interval after treatment with quinacrine. In this study, no advantage of SN 6,911 over quinacrine was found.

From similar observations in studies carried out at various U.S. naval installations, similar conclusions were drawn. Single doses of 1.0 gm. SN 6,911 were found effective in terminating acute attacks of vivax malaria of Pacific origin in 45 patients. Parasitemia was controlled within 36 hours, and usually no further paroxysms occurred. Relapses were observed in as little as 24 days after therapy. Toxic symptoms or signs were not encountered.

No extensive studies on treatment with SN 6,911 for malaria caused by P. falciparum were carried out in the field. In India, it was shown that a single infusion of 0.64 gm. of SN 6,911 in 1,000 cc. of saline given intravenously during 2 to 3 hours was effective in terminating acute attacks of falciparum malaria. Twenty Chinese soldiers were so treated, and within 1 to 4 days (average 2.5 days) blood smears became negative. Fever was controlled in 12 to 80 hours (average 41 hours). The response was comparable to that observed in 20 patients who were given 0.6 gm. of quinacrine intravenously although the latter became fever free on the average of 12 hours sooner than those treated with SN 6,911. In the United States, it was shown that 0.9 gm. of SN 6,911 administered for 1 day followed by 0.3 gm. daily for 6 days effected definitive cure in induced falciparum infections.

Suppression-Studies with SN 6,911 were carried out in Australia on volunteers infected by mosquitoes with the New Guinea strains of P. vivax and P. falciparum, the method of approach being the same as previously described. Volunteers who received "build-up" doses of SN 6,911 of 0.2 gm. twice daily for 4 days before exposure to infection and then had 0.1 or 0.2 gm. daily during the period of exposure and for 23 days after the last infective bite had smears completely parasite free (except one patient who had one parasite on 1 day only), and they had no attacks of malaria. Following discontinuance of suppressive medication, all volunteers infected with P. vivax developed acute attacks (average 27 days), but none of those infected with P. falciparum developed malaria within 92 days after discontinuance of the drug. In the latter group, cure was demonstrated by failure to


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produce malaria in recipients who were given 200 cc. of blood from the test subjects. No immunity was demonstrated since subsequently it was possible to induce malaria in the same subjects with the same strain of falciparum parasites. Subinoculation of blood from subjects treated with SN 6,911, on the eighth and ninth days after reinfection with P. falciparum produced malaria in the recipients. These studies therefore showed that SN 6,911 was curative in falciparum infections through its effect on the parasites after they reached the peripheral blood.

In an experiment of simulated field type, volunteers were heavily exposed to infection for 58 days while suppressive doses of 0.1 gm. SN 6,911 were given daily; this dosage was continued for 28 days after the last infective bite. In addition, the men were subjected to extreme exercise, cold, and adrenalin injections. During the period of exposure and continued suppression, no parasitemia or clinical malaria occurred. After the drug was stopped, malaria developed in all volunteers infected with P. vivax and in none of those infected with P. falciparum. Control studies with similar doses of quinacrine gave identical results.

Toxicity

No toxic manifestations related to SN 6,911 were reported from these studies in which more than 200 patients were given 3.2 gm. of drug during 7 days' treatment for acute attacks of vivax malaria. There were no toxic signs or symptoms in subjects who received 0.1 or 0.2 gm. daily for suppression for several weeks or months nor were any noted in subjects who received 0.4 gm. daily for 20 or more days. No skin discoloration was observed.

Convulsions occurred during the administration of SN 6,911 in three patients with general paresis and malaria. Acute confusional psychosis was observed in two additional patients with plasma concentrations over 400 μg. per liter. One patient who had 1.5 gm. of SN 6,911 intravenously after a preliminary full therapeutic course of quinacrine developed a convulsion. The drug was given in a 2.5 percent saline solution, injected at the rate of 1 cc. per minute. Plasma levels in the order of 1,000 μg. per liter at the end of the injection and levels above 200 μg. 24 hours later were observed in other patients who received similar amounts of SN 6,911 intravenously.

Experience with SN 6,911 was not sufficiently prolonged or extensive to permit the accumulation of data with regard to more chronic toxic manifestations of the nature reported from prolonged quinacrine administration. However, it is of interest that stimulation of the central nervous system was demonstrated in subjects with high plasma levels of SN 6,911.

Summary

SN 6,911 was found to be as effective as quinacrine, except for the briefer interval between relapses after cessation of treatment, but was in no way superior to quinacrine, except that it did not discolor the skin. It might have proved a useful substitute had there been a serious breakdown in the


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use of quinacrine because of alleged or proved toxicity. These studies stimulated further syntheses and alterations of various 4-amino acid compounds which ultimately resulted in a drug that was, in fact, superior to quinacrine. This was SN 7,618, or Chloroquine Diphosphate.

Chloroquine Diphosphate (SN 7,618)57

An intensive 2-year study was made of this drug in man and in experimental animals. Its pharmacology was studied in fairly extensive experiments with mice, rats, dogs, monkeys, and man. Extensive studies were made on its prophylactic activity against domestic strains and Southwest Pacific strains of vivax malaria, on its curative activity against sporozoite-induced infections when administered alone and in combination with other compounds, and on its suppressive activity. Large-scale investigations of its use in terminating the acute attack and for suppression were carried out in military installations. Most of these studies were made in comparison with quinine.

General properties

Absorption of SN 7,618 from the gastrointestinal tract is complete or nearly complete, and somewhat more rapid than absorption of quinacrine. Like quinacrine, SN 7,618 is metabolized in the body. Only 10 to 20 percent is excreted unchanged in the urine; this fraction can be increased by acidification of the urine, decreased by alkalinization. On any given dosage schedule there are substantially higher concentrations of SN 7,618 in the plasma, since there is less localization in the tissues than there is with quinacrine. The pattern of distribution is in general similar. SN 7,618 is concentrated in nucleated cells (also in leukocytes); the liver, spleen, kidneys, and lungs contain from 200 to 500 times the amount in the plasma, while the brain and spinal cord contain no more than 10 to 25 times the plasma concentration.

The marked localization of this drug in the organs, together with the slow rate of excretion and degradation, necessitate a priming dose if the desired concentration in the plasma is to be rapidly reached and maintained. As with quinacrine, these factors result in slow disappearance of the drug from the body when it is discontinued; its concentration in the body fluids generally falls about 60 percent per week when administration stops.

Antimalarial activity

SN 7,618 proved more active than quinacrine in all of the avian malarias in which it was tested. In Plasmodium cathemerium both in the canary and in the duck it is 3.5 times as active as quinacrine, 5 to 13 times as active against Plasmodium gallinaceum and 2.5 times as active in Plasmodium lophurae in the duck. Like quinacrine, it does not produce permanent cures in any of these infections, nor is either drug prophylactic in sporozoite-

57Formula: 7-Chloro-4-(4-diethylamino-1-methylbutylamino) quinoline diphosphate.


563

induced cathemerium malaria in the canary or gallinaceum malaria in the chick.

SN 7,618 is highly active against the erythrocytic forms of P. vivax and P. falciparum. It does not prevent relapses in vivax malaria even in doses many times those required to terminate an acute attack, nor will it prevent the establishment of a vivax infection when administered as a prophylactic. It is highly effective as a suppressive agent and in the termination of the acute attack, significantly lengthening the interval between treatment and relapse beyond that observed with quinacrine or quinine. In falciparum malaria it has been shown to suppress the acute attack and to effect complete cure of the infection. Studies of the antimalarial activity of SN 7,618 against well-standardized strains of P. vivax and P. falciparum have shown it to be approximately three times that of quinacrine. In well-tolerated therapeutic doses a great majority of patients will be afebrile within 24 hours and the remainder within 48 hours. Thick smears for parasites will generally be negative at 48 to 72 hours.

Mean plasma levels in the range of 10 μg. per liter have been shown to be effective in treating attacks of induced vivax malaria. Initial oral doses of as little as 100 mg. followed by daily doses of 85 mg. for 4 days produce plasma levels above the therapeutic range and result in termination of the attack. The therapeutic level for terminating attacks due to P. falciparum are in the range of 20 μg. per liter and such levels and clinical effects have been produced with initial doses of as little as 150 to 300 mg. followed by daily doses of approximately the same amount for 4 to 6 days. It is evident from these observations that the antimalarial activity of SN 7,618 is significantly greater than quinacrine both on the basis of oral dosage and plasma drug concentration.

Clinical testing

SN 7,618 has been given to more than 1,000 patients with acute attacks of vivax malaria of domestic, Pacific, and Mediterranean origin. The clinical testing of this drug in vivax malaria of war origin was carried out principally at Harmon and Moore General Hospitals, designated as specialized treatment centers in the United States for the study of tropical diseases. Other studies in the U.S. Army with SN 7,618 were carried out overseas. In addition, clinical and toxicologic investigations were conducted at various naval, Federal, and civilian installations in this country and abroad as well as by investigators of Allied Nations.

The observations on the use of SN 7,618 in the treatment of vivax malaria reported from Moore General Hospital,58 summarized in the following paragraphs, are representative of other reported studies.

58Most, H., London, I. M., Kane, C. A., Lavietes, P. H., Schroeder, E. F., and Hayman, J. M., Jr.: Chloroquine for Treatment of Acute Attacks of Vivax Malaria. J.A.M.A. 131: 963-967, 20 July 1946.


564

STUDY AT A SPECIALTY CENTER

Material and methods-The patients were military personnel who had acquired vivax infections in the Pacific area or Mediterranean theater. All phases of the disease, first attacks as well as early and late relapses, were represented by significant numbers of men. Approximately 50 to 75 patients were included in each of the five treatment plans.

All patients with an acute clinical attack were admitted to two special-study wards for observation and therapy with SN 7,618. No patient was treated unless his blood smear was positive for malaria parasites and his temperature over 100 F. Cases were selected only with respect to the geographic origin and age of the disease, to ensure adequate representation on each treatment schedule.

All treatment was begun on the morning following the onset of the current attack. Parasite counts were done twice daily and continued until negative for 3 consecutive days. The plasma levels of SN 7,618 were ascertained frequently during and after treatment to determine the pattern of accumulation, stabilization, and disappearance of the drug from the plasma. Temperatures were taken every 4 hours during treatment and every 15 minutes during a paroxysm. The clinical response was followed during daily rounds. All signs and symptoms possibly related to malaria or to treatment with SN 7,618 were recorded. In addition, clinical and laboratory observations were directed specifically to recognizing possible toxic manifestations. All drugs were administered by a medical officer.

Following completion of treatment and study on the wards, the patients were transferred to a convalescent area on the hospital grounds for observation until relapse or for 120 days from the last day of treatment.

During this interval smears were examined twice weekly. In the event of parasitemia the temperature was recorded three times daily and smears made every day. A temperature rise of over 100 F. by mouth associated with a positive smear was considered a relapse, and the patient was readmitted to a ward for further observation and treatment. Approximately 80 percent of the relapsed cases were direct admissions from the convalescent area following paroxysms with temperatures of from 103 to 105 F. The other 20 percent were admitted as a result of temperature observations made during interval parasitemia. Of the latter group at least one-half developed paroxysms shortly after admission to the ward. No patient was treated without coincident fever and parasitemia.

Treatment plans-Protocols for treatment schedules were furnished by the Office of the Surgeon General. Representative treatment schedules which have been found most satisfactory are presented in table 74. (Tablets of 0.1 gm. and 0.3 gm. of SN 7,61859 were available and were used singly or in combination to supply the proper individual dose.)

Other treatment plans consisting of the administration of a total of 0.8 gm. during 7 days and 1.5 gm. during 3 days were also studied.

59The dosage, wherever it appears in this chapter, is in terms of base. This drug was not commercially available at the time these studies were made, and the tablets were specially prepared.-H.M.


565

TABLE 74.-Representative treatment schedules for chloroquine

Schedule


Hour

Dosage (grams)

Plan A:

 

 

    

1st day

8 a.m.

0.4

 

12 m

0.3

 

5 p.m.

0.3


Total

---

1.0

Plan B:1

 

 

    

1st day

8 a.m.

0.3

 

12 m

0.3

    

2d day

8 a.m.

0.3

    

3d day

8 a.m. 

0.3

    

4th day

8 a.m.

0.3


Total

---

1.5

Plan C:

 

 

    

1st day

8 a.m.

0.4

 

12 m 

0.2

 

5 p.m. 

0.2

    

2d day

8 a.m.

0.2

    

3d day

8 a.m.

0.2

    

4th day

8 a.m.

0.2

    

5th day

8 a.m.

0.2

    

6th day

8 a.m.

0.2

    

7th day

8 a.m.

0.2


Total

---

2.0


1This schedule advocated for routine use.

Results.-These results are as follows:

1. Control of parasitemia.-The rate of disappearance of parasites from the peripheral blood during the administration of SN 7,618 in comparison with quinine and quinacrine are shown in chart 31. It may be seen that the peripheral blood becomes free of parasites more rapidly with SN 7,618 (plans A, B, and C) than with either of the other drugs, the difference being more marked between SN 7,618 and quinine than between SN 7,618 and quinacrine. The superiority of SN 7,618 was manifest in vivax malaria of Mediterranean or Pacific origin in first attacks as well as in relapses occurring at any stage of the disease.

2. Control of fever.-In a total of 244 attacks treated with SN 7,618 according to plans A, B, and C, only 5 patients or 2.1 percent had fever (temperature of 100 F. or more) the day after treatment was begun or subsequently. By contrast, treatment with quinine in 184 attacks and with quinacrine in 391 attacks was associated with fever on the second day or later in


566

CHART 31.-Comparative rate of disappearance of parasites from peripheral blood during treatment of vivax malaria with quinine (172 attacks), quinacrine hydrochloride (397 attacks), and chloroquine (293 attacks)

8.7 and 8.0 percent, respectively, of patients treated. The superiority of SN 7,618 in this respect is manifest in infections of both Mediterranean and Pacific origin, regardless of the initial parasite density, and in Pacific infections regardless of whether the attack is the very first or a relapse at any stage of the disease. In delayed primary attacks the proportion of patients who have fever on the second day after treatment with SN 7,618 is begun is higher than in patients treated in relapse. This is also true even to a greater extent for delayed primary attacks treated with quinine or quinacrine, shown in chart 32.

3. Control of symptoms.-It is difficult to evaluate comparative effects of quinine, quinacrine, and SN 7,618 in controlling symptoms which are usually present for a few days in a treated attack of malaria. However, clinical impressions based on treatment of more than 1,000 acute attacks of vivax malaria and supported by a more detailed statistical analysis, indicate that SN 7,618 is at least as good as quinine or quinacrine in the control of all symptoms, and is superior to one or the other in the control of some symptoms.

Headache and backache are relieved more rapidly with SN 7,618 or quinine than with quinacrine. Quinine is more effective than quinacrine in the control of generalized aching, but is not significantly better than SN 7,618. Weakness, dizziness, and lightheadedness disappear more rapidly with SN 7,618 or quinacrine than with quinine. Nausea persists longer in patients treated with quinine than in those treated with SN 7,618 or Atabrine. The effect of each of these drugs on the duration of vomiting, abdominal pain, and abdominal tenderness is essentially the same.


567

CHART 32.-Comparative efficiency of quinine, quinacrine hydrochloride, and chloroquine in controlling fever during treatment of delayed primary attacks of relapses of vivax malaria

4. Effect on interval to relapse.-Quinine, quinacrine, and SN 7,618 do not materially influence the ultimate relapse rate following treatment of the acute attack. Apparently the ultimate relapse rate in large groups is not affected by the age of the disease, the number of previous attacks, total amount of drug, or duration of treatment. More than 500 patients treated for acute attacks of vivax malaria of Pacific and Mediterranean origin were followed to relapse, or for a minimum of 120 days. The relapse rates following treatment with quinine, quinacrine, or SN 7,618 were from 75 to 85 percent for Pacific infections and approximately 35 percent for Mediterranean infections. The cumulative relapse rates following treatment of acute attacks of vivax malaria of Pacific origin are shown in chart 33. At 120 days, 85, 80, and 70 percent of patients treated with quinine, quinacrine, and SN 7,618, respectively, had relapses.

The interval to relapse, however, and the distribution of the relapses that occurred during the first 2 months after treatment are strikingly different for the three drugs. These differences are presented in chart 34.

During the first month after treatment, 54 percent of the patients treated with quinine relapsed, 9 percent relapsed after quinacrine, and none relapsed after SN 7,618. At 40 days, relapses following SN 7,618 begin to occur, but these represent less than 1 percent of treated patients, whereas 67 and 28 percent relapsed at 40 days after treatment with quinine and quinacrine, respectively. At 50 days, 72, 40, and 11 percent of the patients relapsed after quinine, quinacrine, and SN 7,618, respectively.

In terms of the total number of relapses that occur within 120 days, the percentages of patients who relapsed within 50 days were 85, 50, and 16 percent, respectively, for quinine, quinacrine, and SN 7,618. Thus, of the total relapses that occur within 120 days, more than three-fourths of them will take place in the first 50 days after quinine,


568

while during the same time after quinacrine only one-half, and after SN 7,618 only one-sixth will occur. The median interval to relapse following treatment with quinine is 24 days, with quinacrine, 50 days, and with SN 7,618, 61 days.

CHART 33.-Cumulative rates of relapses during a minimum of 120 days following treatment of acute attacks of vivax malaria with quinine (76 patients), quinacrine hydrochloride (118 patients), and chloroquine (156 patients)

Since none of these drugs produces a complete cure of malaria, the drug of choice on the basis of interval to relapse is the one that gives the longest mean interval, the greatest median interval for a large group of patients, and the smallest number of short-term relapses. The data presented show that the interval to relapse after treatment with SN 7,618 will be on the average at least 5 weeks longer than after quinine and about 2 weeks longer than after quinacrine. Only a negligible number of patients treated with SN 7,618 will relapse during the first 50 days after treatment. Accordingly, SN 7,618 not only controls symptoms, fever, and parasitemia promptly but, in addition, confers freedom from another attack for a period of approximately 2 months.

Plasma levels-Blood was drawn at such times as to determine the rate of accumulation, stabilization, and disappearance of SN 7,618 from the plasma during and after treatment with various dosage regimens. The values obtained during and after treatment on schedules A, B, and C are presented in chart 35.

The minimal plasma concentration of SN 7,618 that is effective in terminating an acute attack has been shown to be in the range of 10 μg. per liter. The levels observed during and after treatment on plans A, B, or C are well above this range.

No correlation has been found between variations observed in levels obtained in single individuals receiving the same amount of drug and their interval to relapse or to the first parasitemia after completion of treatment.


569

CHART 34.-Comparison of distribution of relapses occurring during the first 60 days after treatment of acute attacks of vivax malaria of Pacific origin with quinine, quinacrine hydrochloride, and chloroquine

Summary.-The data presented in the study on the relative efficiency of quinine, quinacrine, and SN 7,618 are summarized and presented for reference in table 75.

TABLE 75.-Relative efficiency of quinine, quinacrine hydrochloride, and chloroquine in treatment of acute attacks of vivax malaria

Efficiency factors

Quinine

Quinacrine hydrochloride


Chloroquine 
(SN 7,618)

Total amount of drug.....grams...

28.35

2.8

11.0, 1.5, 2.0

Duration of treatment.....days...

14

7

11, 4, 7

Rate of parasite clearance

+

+++

++++

Control of fever:

 

 

 

    

Delayed primary attacks2

+

++

+++

    

Relapses3

++

++

++++

Interval to relapse:

 

 

 

    

Median.....days...

24

50

61

    

Relapses:

 

 

 

         

First 50 days.....percent...

85

50

16

         

Total, 120 days...do...

90

82

75

Control of symptoms

++

+++

++++

Toxicity

4+++

5+

6+


1Plans A, B, and C. See table 74. 
2Infections of Pacific origin.
3Infections of Mediterranean or of Pacific origin. 
4Cinchonism.
5Eczematoid reactions in patients sensitive to quinacrine hydrochloride. 
6Slight, transitory pruritus; rare erythema or urticaria.


570

From this study it was concluded that SN 7,618 is a highly effective, safe antimalarial drug which is superior to quinine and quinacrine in the treatment of acute attacks of vivax malaria. Routine treatment was recommended as follows:

One tablet (0.3 gm.) of SN 7,618 is administered when the diagnosis of vivax malaria is established by a positive blood smear. This amount of drug (0.3 gm.) is repeated 4 hours after the first dose. One tablet (0.3 gm.) is then given on each of the following three mornings. The total dose is 5 tablets, totaling 1.5 gm. of SN 7,618 administered during 4 days.

CHART 35.-Average plasma levels of chloroquine (176 patients) during and after treatment under plans A, B, and C

OTHER STUDIES OF VIVAX INFECTIONS

Treatment plans with SN 7,618 in which total doses of 1.0 gm. in 1 day, 0.8 gm. in 6 days, 2.0 gm. in 6 days, and 1.2 gm. in 3 days were studied at Harmon General Hospital. The results reported from a total of 235 attacks treated on the above schedules were essentially the same as those reported from the Moore General Hospital. Treatment of primary attacks of Pacific origin or relapses of Pacific or Mediterranean vivax malaria with SN 7,618 resulted in prompt control of symptoms. Parasitemia and fever disappeared more promptly than with quinacrine, and the interval to relapse was greater


571

than with the latter except in the patients who had a total of only 0.8 gm. of SN 7,618 during 6 days. It was felt that SN 7,618 was superior to other antimalarial agents previously studied at that installation (quinine, quinacrine, and SN 6,911).

A single dose of 1.0 gm. SN 7,618 was administered to each of 50 patients with acute attacks of vivax malaria at a U.S. naval installation. There was prompt subsidence of fever, and parasites disappeared in all cases within 36 hours. The interval to relapse from this single-dose schedule was longer than that following the standard quinacrine course. At another naval installation, more than 100 patients were treated with SN 7,618 for acute attacks of vivax malaria of Pacific origin. The majority received 1.0 gm. within a period of 16 to 24 hours. Control of symptoms and fever was more prompt than was observed in patients treated with quinacrine, and parasites disappeared from the blood in most cases within 48 hours. Short-term relapses, that is, less than 40 days, did not occur after treatment with SN 7,618, in contrast to a significant number of relapses in less than 40 days after treatment with quinacrine.

SN 7,618 was used clinically to terminate acute attacks of vivax malaria in various oversea areas. In India, 26 American military patients with acute vivax infections were treated with 0.9 gm. during the first 24 hours followed by a single dose of 0.3 gm. on each of the 2 successive days (total 1.5 gm. in 3 days). The average duration of fever was 24.1 hours and parasitemia 1.5 days. In Peru, more than 300 natives were treated for acute attacks of vivax, falciparum, and mixed malaria with relatively small doses of SN 7,618 (0.75 gm. on the first day and 0.25 gm. on the second day; total 1.0 gm. in 2 days). In 70 cases carefully studied, blood smears were positive in only 17 and 5 at 24 and 48 hours, respectively, after the initiation of therapy. The clinical response to treatment was considered good in the majority of patients. It was noted the falciparum infections responded more slowly than those due to P. vivax.

STUDIES OF FALCIPARUM INFECTIONS

SN 7,618 did not have any extensive clinical trial in the treatment of falciparum infections, particularly the fulminating variety with cerebral involvement. Preliminary studies in this country with injections of domestic strains of P. falciparum indicated that plasma concentrations of 20 μg. of drug per liter maintained for 4 to 6 days resulted in the control of fever and parasitemia without recurrence of symptoms or signs of infection for 14 days or more. Such relatively low plasma levels are easily obtained with initial doses of 200 mg. and maintained with daily doses of 100 mg. In actual practice, the oral dosage schedules of 0.6 to 1.0 gm. during the first 24 hours followed by daily doses of 0.2 to 0.3 gm. result in plasma levels of 5 to 10 times that required to terminate falciparum activity. It is probable therefore that SN 7,618 would prove effective in terminating most infections with P. falciparum.


572

At the 20th General Hospital in the India-Burma theater, 10 Chinese soldiers with acute falciparum malaria were treated with 1.5 gm. of SN 7,618 during 3 days. Clinical response was satisfactory in all patients. The average duration of fever (102 to 105 F. at onset) was 34 hours after the first dose (range 8 to 64 hours), and blood smears became negative within 3 days. In another report from the same hospital, similar results were recorded in eight American soldiers with acute falciparum malaria treated with SN 7,618 (total 1.5 gm. during 3 days). The average duration of fever (102.4 to 104.8 F. at onset) was 28.4 hours after the first dose, and blood smears were free of parasites within 1 to 3 days.

In the Peru study of more than 300 acute attacks of malaria (many P. falciparum or mixed vivax-falciparum) treated with a total of 1.0 gm. of SN 7,618 during 2 days, 17 infections with P. falciparum and 7 mixed cases were closely followed; the response to treatment was considered rapid or good. There were no treatment failures. Fever and parasitemia were quickly controlled. In general, the rapidity of disappearance of parasites and the clinical response to treatment varied with the severity of the infection. It should be borne in mind that the total duration of treatment and total doses of drug employed were no optimum and that the satisfactory response was observed in highly immune natives who are not comparable with nonimmune American troops.

Unfortunately, no parenteral SN 7,618 was available, and no opportunity was afforded for comparing the relative efficiency of SN 7,618 and parenteral quinine or quinacrine in the treatment of fulminating falciparum infections complicated by severe vomiting or involvement of the central nervous system.

STUDIES OF SUPPRESSION

The suppressive efficacy of SN 7,618 and the mode of its action against vivax and falciparum infections were investigated in Australia in the manner of similar studies of quinine, quinacrine, and SN 6,911.60 New Guinea strains of P. vivax and P. falciparum were employed. The "build-up" doses of SN 7,618 were 0.2 gm. twice daily for 4 days. Subsequently, the daily dosage was 0.1 gm. continued for 23 days after the last exposure to infective mosquitoes. None of the volunteers infected with P. vivax or P. falciparum developed clinical malaria or microscopically detectable parasitemia during the period of suppression. However, subinoculation of 200 cc. of blood to other volunteers 9 or 10 days after infection produced malaria in the recipients. This proved that the test subjects were infected and demonstrated that the action of SN 7,618 was not prophylactic and that its suppressive action against the parasites was exerted after their appearance in the blood. Following discontinuance of medication, all volunteers infected with P. vivax developed malaria within 40 to 60 days, but no falciparum malaria developed during a

60 See footnote 12, p. 529.


573

period of 81 days in the men infected with P. falciparum. SN 7,618 was thus shown to be equally as effective as quinacrine or SN 6,911 in suppressing both vivax and falciparum infections and in curing the latter.

Anticipating the practical application of SN 7,618 as a suppressive agent, one must consider the persistence of this drug in the body and the fact that relatively low plasma levels (10 μg. per liter) have pronounced antimalarial activity. It was shown that the administration of 0.3 gm. of SN 7,618 in single doses once a week resulted in the maintenance of mean levels above 10 μg. per liter in the majority of more than 50 subjects who remained on this suppressive schedule for 4 to 8 weeks.

Suppressive schedules of single weekly doses of SN 7,618 were studied, in this country, in patients with recurrent vivax malaria of Pacific origin. Ninety-four men who previously were having frequent relapses were placed on 0.3 gm. weekly for approximately 3 months. During the period of suppression, only one man had a positive blood smear on one occasion. During the last 10 days of suppression, 75 men were placed on an extremely rugged test of physical endurance, consisting of daily hikes of 5 to 15 miles over very rough terrain, forced marches, and rifle drill. In this period. six men developed transient parasitemia. No clinical attacks occurred during suppression, including the period of exercise. It was calculated on the basis of the number of attacks these men had had in 3 months prior to suppression that at least 75 relapses should have occurred if no suppressive therapy had been taken. It was thus shown that SN 7,618 given once a week was completely effective in suppressing clinical malaria in a group with a high index of relapse and parasitemia (positive smears in 84 percent in the 5-week period prior to suppression).

At Moore General Hospital, more than 100 patients who had had an attack of vivax malaria within the previous 3 months were placed on 0.3 gm. SN 7,618 once a week for 8 to 16 weeks. More than half of these patients had tuberculosis. During the period of suppression, no parasitemia and no clinical malaria occurred. The patients, especially those with tuberculosis, were reluctant to discontinue their weekly dose of SN 7,618 because they felt reassured that they would not have malaria while they were taking the drug.

In a series of more than 200 men treated with 1.0 gm. of SN 7,618 in 1 day for acute attacks of vivax malaria of Pacific origin, the shortest interval to relapse was 33 days. It was therefore believed that successful suppression could be accomplished by the administration of 1.0 gm. in 1 day at monthly intervals. Accordingly, 35 men recently treated for an acute attack with 1.0 gm. of SN 7,618 in 1 day were advised to take 1.0 gm. within 1 day every 4 to 6 weeks. They were observed from 60 to 162 days while on this schedule of self-medication. In this period, the expected number of relapses was calculated to be 24, but only 8 occurred. It is possible that, if medication had been supervised and administered regularly once a month rather than at irreg-


574

ular intervals up to 6 weeks, more effective or complete suppression might have been produced. Thus, SN 7,618 is not only effective as a suppressive with weekly doses of 0.3 gm. but it is possible that satisfactory suppression may result from larger doses at greater intervals.

Studies on suppression with SN 7,618 were made in various areas overseas: In Peru, in more than 1,200 adults and children (natives); in India, in school children, in coolies, and in colored troops; and in the Philippines, in American soldiers during, unfortunately, a time when there was practically no transmission of malaria. Military deactivation of units prevented completion of the last investigation as previously planned. In all these studies, the results were good, but such observations in natives, or in American troops during periods of nontransmission, offered no conclusive evidence that complete suppression under combat conditions in highly malarious areas would result from the administration to troops of a weekly dose of 0.3 gm. of SN 7,618.

The experiments in Australia, the observations on the control of parasitemia overseas, and the suppression of relapses in this country indicate, however, that SN 7,618 in weekly suppressive doses should prove effective under combat conditions. The apparent advantage of SN 7,618 as a suppressive agent lies in the ease of administering it in the form of one tablet once a week, the absence of the yellowish discoloration of the skin resulting from the prolonged use of quinacrine, and its tolerability.

Toxicity

Extensive studies of the acute and chronic toxicity of SN 7,618 were conducted in animals prior to its clinical application in man. Observations were made on the tolerability and toxicity of varying amounts of drug administered to human volunteers, often for prolonged periods. Finally, data collected on possible toxic signs or symptoms during the administration of therapeutic or suppressive amounts of SN 7,618 in several thousand individuals furnished the background for the following statement approved by the Board of Coordination of Malarial Studies:

There is little difference in the toxicity of SN 7,618 and that of quinacrine in experimental animals. The acute toxicity of both drugs given orally is about the same in the rat and monkey. The acute toxicity of intravenous SN 7,618 is greater than that of quinacrine in the dog. Short-term chronic toxicity tests in the mouse show the two drugs are about equally toxic. In such tests carried out in the rat and the monkey for periods not exceeding 30 days, SN 7,618 is slightly more toxic than quinacrine. In longer term studies with the rat and monkey extending up to 120 days, the drugs are about equally toxic or, if anything, SN 7,618 is slightly less toxic than quinacrine.

In man, the symptoms that have been observed following doses of SN 7,618 adequate for treatment of the acute attack include mild and transient headache, visual disturbances, pruritus, and gastrointestinal complaints. In chronic toxicity studies in man using a dose (0.5 gm. weekly) in excess of that necessary for adequate suppression, no serious symptoms and no impairment of health have been observed in 31 subjects over a period of 11 months of consecutive drug administration. In studying the record


575

of 2,655 individuals who have received SN 7,618, every symptom that has been observed has been recorded in an effort to bring out even minimal toxic manifestations. In a small number of instances, usually with dosages higher than necessary for either treatment or suppression, individual subjects have refused to continue drug administration because of unpleasant symptoms; none of these manifestations has been constitutionally serious and all have been readily reversible. Unlike quinacrine, SN 7,618 does not discolor the skin.

Statements on toxicity in various reports concerned with the therapeutic or suppressive use of SN 7,618 will be briefly cited.

In a treatment study61 in which 365 patients with acute attacks of vivax malaria were given total doses of 0.8 to 2.0 gm. of SN 7,618 during a period of 1 to 7 days, no major toxic manifestations were encountered clinically or in numerous laboratory investigations. It was not necessary to interrupt or discontinue treatment in a single case. Occasionally, there was mild nausea if the drug was taken in the fasting state. No visual disturbances were noted. Particular effort was made to detect cutaneous symptoms or signs that might be attributed to SN 7,618, and special questioning elicited information that would rarely have been volunteered. Of the 284 patients treated with SN 7,618, 56 complained of pruritus during the course of drug administration. The pruritus was occasionally generalized but more often localized, particularly to the palms and soles, and in the great majority it was transitory and very mild. Of the 56 patients who developed pruritus, 50 had no coincident skin eruptions. Seven patients, or only 2.4 percent of the total number treated, developed erythema, urticaria, or a mild papular eruption. No similar emphasis was placed on skin symptoms in patients treated with quinine or quinacrine and it is likely that the reported incidence in association with SN 7,618 therapy is disproportionately high. In this study, the administration of SN 7,618 to patients with eczematoid dermatitis or the eczematoid-lichen-planus complex due to quinacrine did not result in exacerbation of the underlying skin condition in any case.

In another series of 236 patients treated with similar total doses of SN 7,618 the incidence of pruritus was 7 percent but urticaria or rash occurred only in 3 cases. Visual disturbances were not encountered. Gastrointestinal symptoms were negligible.

Visual disturbances, that is, blurred vision and difficulty in shifting fixation from near to distant objects, have been described in volunteers on daily doses of 0.5 gm. SN 7,618 and in patients treated for acute attacks of vivax malaria with 3.2 gm. These symptoms are undoubtedly of importance in evaluating the toxicity of SN 7,618 since they originate in the central nervous system. It must be pointed out, however, that symptoms or signs have not occurred in almost 1,000 patients treated with total doses of less than 2.0 gm. or with suppressive doses of not more than 0.3 to 0.5 gm. per week. The amounts of SN 7,618 reported to have produced visual disturbances are in the order of 10 times that required for adequate suppression and 2 to 4 times the required dose for termination of an acute attack.

In the field studies of suppression that have been cited, based on several thousand subjects, no striking toxicity is noted, and the incidence of gastrointestinal or other symptoms requiring the discontinuance of the drug is remarkably low. Detailed investigations of the effects of SN 7,618 suppression on various organ functions were carried out at Randolph Field, San Antonio, Tex. Doses of 0.5 gm. weekly and twice weekly

61See footnote 58, p. 563.


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were given for 4 weeks. No significant effects on physical fitness, on psychological performance at ground level and at 18,000 feet, on vision (as indicated by scotopic vision, visual fields, or near-point accommodation), on auditory acuity, on heart (as indicated by electrocardiograms), or on ability to retain balance while blindfolded, were observed.

Observations on the prolonged administration of SN 7,618 were made in conscientious objectors. Forty men given 0.3 gm. daily for 77 days and then 0.5 gm. weekly for 12 weeks showed no serious toxic reactions. Headache and difficulty in quickly fixing on distant objects occurred in this group on very large doses. Visual symptoms persisted in only 2 men of 31 who remained on the drug for 9 months. Bleaching of the hair at the roots was observed in five blonde subjects while they were receiving 0.3 gm. of SN 7,618 daily. The color of the hair returned to normal when the drug was discontinued. One patient given SN 7,618, 0.5 gm. weekly, for 8 months developed an eruption resembling lichen planus which persisted during the subsequent administration of the drug and began to subside 2 weeks after its discontinuance.

The last observation is of extreme importance in that it suggests the possibility that the prolonged administration of SN 7,618 in large doses may result in the dermatitis complex (eczematoid dermatitis and/or lichen planus) described with quinacrine suppression. In this connection it is of interest that of 30 patients with atypical lichen planus who were placed on suppression doses of SN 7,618 in the India-Burma theater (0.3 gm. weekly), one suffered an actual flareup of the dermatitis described as a mild acute eczematoid reaction which came on after one dose and disappeared within 2 days. It must be remembered that patients with eczematoid dermatitis may react to many drugs. At Moore General Hospital more than 50 patients with atypical lichen planus and a like number with eczematoid skin conditions were given SN 7,618 for termination of acute attacks of malaria. There was no exacerbation in the skin disease in these cases, and in a group of patients with lichen planus who continued on suppressive therapy of 0.3 gm. weekly up to 3 months, no change was noted in the lichenoid lesions other than continued regression.

The toxic manifestations of SN 7,618 may be summarized briefly. Little to no toxicity was encountered with therapeutic (1.0 to 2.0 gm.) or suppressive (0.3 gm. weekly) doses of SN 7,618. Minor toxic symptoms consisted of occasional gastrointestinal complaints and pruritus in a small number of subjects. Following large doses for therapy or suppression, visual disturbances occurred, and in one case atypical lichen planus developed after suppressive medication for 8 months (0.5 gm. weekly). In general, it was felt by most observers that SN 7,618 in recommended doses was a safe drug.

Summary

Clinical experience with SN 7,618 proved this drug to be a highly effective antimalarial agent, superior to quinacrine, quinine, and SN 6,911. It excels quinacrine and quinine in more prompt control of fever, symptoms, and parasitemia, in a shorter course of treatment, in a longer interval to relapse, in the abolition of short-term relapses, and in freedom from major toxic reactions. Given in single weekly doses, SN 7,618 is able to provide effective suppression against vivax and falciparum infections and to cure the latter. SN 7,618 does not discolor the skin. Unfortunately, no assay of its value in fulminating falciparum infections was possible. Experience has shown SN 7,618 to be a safe drug.


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Oxychloroquine (SN 8,137)62

General properties and antimalarial activity

The absorption, degradation, distribution, and antimalarial properties of SN 8,137 are essentially similar to SN 7,618 although it appears to have less antimalarial activity in oral dosage. The greater persistence of SN 7,618 in the body is reflected in the smaller weekly dose required of this drug than of SN 8,137 for comparable suppressive effects. The latter appears to be less toxic, but this advantage may be offset by the larger doses necessary for equivalent suppressive action.

The estimated "critical" plasma levels of SN 8,137 necessary for terminating clinical activity and parasitemia due to P. vivax and P. falciparum have been shown to be approximately 17 and 19 μg. per liter, respectively. In induced experimental malaria, total doses of 0.3 gm. for vivax infections and 0.6 gm. for falciparum infections have given the mean plasma levels in the order of 25 to 50 μg. per liter in the falciparum infections and 17 to 31 μg. per liter in the vivax infections. It is apparent therefore that relatively greater doses and higher plasma levels are required for equivalent antimalarial activity than with SN 7,618. Single weekly doses of 0.25 gm. of SN 8,137 for 4 weeks were found effective in suppressing vivax (domestic strain) infections transmitted by mosquitoes, whereas weekly doses of 0.125 gm. were ineffective.

No toxicity was reported in 16 volunteers who were given SN 8,137 daily for 6 weeks. The dosage in the sixth week was 600 mg. daily and the total dosage per man during the entire period was 12.2 gm. or an average of 0.3 gm. daily for 42 days. Headache, anorexia, and visual disturbances occurred with moderate frequency in subjects receiving similar amounts of SN 7,618, particularly if the plasma levels were above 275 μg. per liter.

Clinical testing

SN 8,137 had only limited clinical application in the treatment of malaria in the U.S. Army. At Harmon General Hospital, 63 patients with acute attacks of vivax malaria were treated with total doses of 2.0 gm. in 3 days (1.0 gm. on the first day and 0.5 gm. on each of the next 2 days). A greater number of patients treated with SN 8,137 had fever on the second day of treatment than had groups treated with SN 6,911, SN 7,618, or quinacrine. Parasite clearance was not as rapid during the first 24 hours of treatment as with quinacrine or SN 7,618, although more rapid than with quinine or SN 6,911. In the next 48 hours, the parasite clearance rate was about the same for SN 8,137 as for the other 4-aminoquinolines as well as quinacrine. Toxic symptoms with SN 8,137 in this study appeared more frequently than with the other synthetic drugs used. There was nausea, vomiting, anorexia,

62Formula: 7-Chloro-4-(3-diethylamino-2-hydroxypropylamine) quinoline diphosphate.


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and abdominal cramps in a total of four patients, diarrhea in five patients, pruritus in four patients, urticaria and a rash in two patients, and dizziness in four patients.

Although the patients were not retained for determination of the interval to relapse, six patients did relapse within 31 to 39 days after completion of treatment. It appears from this small amount of data that SN 8,137 is inferior to SN 7,618 in its poorer control of fever, slower parasite clearance, shorter interval to relapse, and greater toxicity.

Summary

SN 8,137 has not been studied as extensively as other 4-aminoquinoline compounds. Despite the fact that it appears to have considerable antimalarial activity, although less than SN 7,618, it is doubtful if it offers any advantage over the latter. In the treatment of acute attacks, SN 8,137 proved to be inferior and more toxic than SN 7,618. As a suppressive agent, SN 8,137 may possibly have some value because of its apparent tolerability in relatively large doses. On the other hand, its rapid disappearance from the body compared to SN 7,618 may require doses of an order to offset its alleged tolerability.

Summary of Studies

As a result of extensive clinical and pharmacological studies with these drugs, compounds were found that could be substituted, if necessary, for quinacrine without sacrificing any of the advantages of the latter in the treatment or suppression of malaria. In addition, one of the derivatives of this group of drugs (SN 7,618 or chloroquine) proved superior to quinacrine and other drugs both for treatment and suppression. The 4-aminoquinolines were found to cure falciparum infections and to be effective as suppressive agents in single weekly doses. They do not discolor the skin and may be taken for prolonged periods without apparent severe toxicity. The relapse rate in vivax infections is not materially influenced by treatment with these drugs, although with SN 7,618 there is a significant prolongation of the interval to relapse and a reduction in the number of short-interval relapses after treatment. Treatment schedules of 1 to 4 days are practical in acute attacks of vivax malaria. Extensive field studies of falciparum infections were not carried out, and this phase of the treatment of malaria requires further investigation. The occurrence of atypical lichen planus during the prolonged administration of SN 7,618 suggests the possibility of the significant development of this syndrome if chloroquine were to be used as widely as quinacrine. The careful and complete clinical and pharmacological studies carried out with these drugs have added much to knowledge of the chemotherapy of malaria.


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8-AMINOQUINOLINE COMPOUNDS

Pamaquine (Plasmochin Naphthoate)63

Historical review

The first promising synthetic antimalarial drug was introduced in Germany in 1924, by Schulemann and his coworkers at Leverkusen. The schizonticidal and gametocidal properties of Plasmochin in experimental hosts and in man were such as to represent a major advance in the chemotherapy of malaria. It was hoped that as a result of continued chemical and pharmacological investigations a less toxic and more curative compound would be found. Actually, as will be demonstrated in this section, Plasmochin if properly used produces definitive cure in infections with strains of P. vivax that have a high index of repeated relapse after all other forms of treatment. The drug-testing program in Germany continued during World War II and resulted in the synthesis and testing of more than 200 of these 8-aminoquinoline compounds. In the United States, similar activity was directed in a search for an 8-aminoquinoline drug that would be superior to Plasmochin, be less toxic, and might be a true causal prophylactic or curative agent in the prevention, suppression, and treatment of malaria. As a result of these studies, a reevaluation of Plasmochin led to its rational and successful use in curing relapsing vivax infections and to the discovery of several compounds that are considered less toxic and in other respects superior to Plasmochin. Certain prewar studies on the clinical application of Plasmochin, reviewed at Moore General Hospital,64 will be described briefly. In addition, clinical studies made during the war that led to the successful use of Plasmochin as a curative agent will be discussed.

Acute attacks of malaria are more effectively and safely terminated by the use of quinine, quinacrine, or the more recently introduced 4-aminoquinoline compounds than by Plasmochin alone. In recent years, Plasmochin has been used almost entirely as an adjunct to other antimalarial therapy because of its ability to eradicate gametocytes of P. falciparum with small amounts of the drug in a matter of a few days. This practice is of questionable value as a control measure in areas where malaria is endemic. There is evidence, however, that simultaneous administration of Plasmochin and quinine daily for 2 weeks or more is highly effective in reducing relapse rates in vivax malaria during an observation period of 2 to 6 months. This is in sharp contrast to curative failure or high relapse rates in malaria caused by Pacific strains of P. vivax after treatment with quinine, quinacrine, or 4-aminoquinoline compounds.

63Formula (pamaquine naphthoate): methylene-bis-β-hydroxynaphthoate of 6-methoxy-8- (1-methyl-4-diethylamino) butylaminoquinoline.
64Most, H., Kane, C. A., Lavietes, P. H., London, I. M., Schroeder, E. F., and Hayman, J. M., Jr.: Combined Quinine-Plasmochin Treatment of Vivax Malaria; Effect on Relapse Rate. Am. J.M. Sc. 212: 550-560, November 1946.


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Prewar studies.-Sinton and Bird,65 in 1928, reported from India on 86 patients given Plasmochin alone or Plasmochin and quinine together for an attack of vivax malaria and observed for 2 to 4 months after treatment. Occasionally, patients failed to complete treatment because of toxic reactions or disappearance from observation. The percentage of relapses was calculated on this basis. Twenty-nine patients were given 0.08 gm. of Plasmochin (probably Plasmochin naphthoate) on 17 treatment days during a period of 39 days as suggested by the German manufacturers of the drug. The relapse rate during the period of observation was 36 percent. Twenty-two patients were given 0.08 gm. on as many consecutive days as possible for 28 treatment days with interruptions only for toxic manifestations, the average treatment period being 36 days with a range from 28 to 53 days. The relapse rate in this group was 23 percent. Fifteen patients were given 0.10 gm. Plasmochin plus 1.25 gm. quinine sulfate on 17 treatment days during a 39-day course of treatment. The relapse rate during 2 to 4 months was 20 percent. Finally, a group of 20 patients received these same daily amounts of both drugs for 28 days as continuously as possible during an average treatment period of 37 days. None relapsed during the period of observation. The relapse rate for the 51 patients who received Plasmochin alone was 30 percent and for the 35 patients who received Plasmochin and quinine together, 8.5 percent. Thus, of the total number of 86 patients who received Plasmochin for 17 to 28 days, the relapse rate as given by the authors was 21 percent. This percentage includes 6 patients who were lost to followup studies or who did not complete the full course of treatment and were counted as failures; the failure rate actually observed in 80 men during a period of 2 to 4 months after treatment was 16 percent. In contrast to this finding, the relapse rate for 111 men treated with quinine alone and similarly observed was 77 percent. There is little question that in this study combined quinine-Plasmochin treatment very substantially reduced the incidence of relapse during 2 to 4 months after treatment.

In 1930, Sinton and his coworkers66 reported two additional groups of patients on combined quinine-Plasmochin treatment for acute attacks of vivax malaria. Seventeen were given, daily, Plasmochin, 0.06 gm., and quinine sulfate, 1.25 gm., from 4 to 21 days. None of them had a clinical or parasitemic relapse during 2 months after treatment, when the experiment was terminated. An additional 44 patients received Plasmochin, 0.04 gm., and quinine, 1.25 gm., daily for 21 days. Three patients relapsed, making a total failure rate of 6 percent for 54 men who had Plasmochin for 14 or more days in contrast to a relapse rate of 42 percent for 38 patients who were treated with quinine alone.

65Sinton, J. A., and Bird, W.: Studies in Malaria, With Special Reference to Treatment. Part IX. Plasmoquine in the Treatment of Malaria. Indian J.M. Res. 16: 159-177, July 1928. 
66Sinton, J. A., Smith, S., and Pottinger, D.: Studies in Malaria, With Special Reference to Treatment. Part XII. Further Researches into the Treatment of Chronic Benign Tertian Malaria With Plasmoquine and Quinine. Indian J.M. Res. 17: 793-814, January 1930.


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In 1932, Jarvis67 reported 8.0 percent relapses during a 2 to 4 months' period of observation of 75 patients who received Plasmochin, 0.03 gm., and quinine, 1.3 gm., daily for 21 days. Manifold68 reported a study of some 3,000 Indian and British troops treated for acute attacks of vivax malaria with Plasmochin, 0.04 gm., and quinine, 1.3 gm., daily for 21 consecutive days. Of these, 98 percent were able to complete the full course of treatment. Analysis of readmission records for 5 months after treatment showed the relapse rate for the whole group was 5.2 percent in contrast to a wide experience of rates from 42 to 77 percent after treatment with quinine alone.

Wartime studies-In 1945, Kelleher and Thompson69 reported observations made during the war on the effects of combined quinine-Plasmochin treatment of vivax malaria of Mediterranean origin. Of 100 patients with delayed primary attacks treated with 4.6 gm. of quinacrine during 12 days, 29 percent relapsed during an observation period of 5 months. Of 76 patients with delayed primary attacks treated for 10 days with Plasmochin base, 0.03 gm., and quinine 2.0 gm., daily, only 14, or 18 percent, relapsed. The relapse rate for 650 men treated with quinacrine as above for later relapses and followed for 5 months was 34 percent, whereas the relapse rate for 584 men treated for later attacks with combined quinine-Plasmochin was 10 percent. In American experience, the relapse rate in 120 days for Mediterranean vivax malaria (150 patients) treated with quinacrine or quinine was 32 percent. There can be no question about the significance of the reduced relapse rate in this British report.

Thus far, references have been cited which indicated that combined quinine-Plasmochin given for at least 10 days, the amounts of Plasmochin base being at least 0.03 gm. a day, is highly effective in reducing the relapse incidence of vivax malaria during an observation period of 2 to 5 months. Small amounts of Plasmochin or short-term schedules are definitely of no value in vivax malaria of Pacific origin, and experiences with such schedules are generally unconvincing. Dieuaide,70 in reviewing relapses following various schedules of treatment in the Pacific area, cites 83 percent within 16 weeks for 185 men who had had two courses of quinacrine hydrochloride for acute attacks of vivax malaria and 78 percent for 136 patients who had had two consecutive courses of treatment consisting of quinacrine (0.1 gm. three times daily for 7 days), followed by Plasmochin naphthoate (0.02 gm. three times daily for 5 days), after which both were repeated. Thus, Plasmochin for 5 days and repeated a week later was not effective in reducing the relapse rate as compared with quinine or various schedules of quinacrine mentioned

67Jarvis, O. D.: Further Researches into the Treatment of Chronic Benign Tertian Malaria With Plasmoquine and Quinine. Indian J.M. Res. 20: 627-631, October 1932.
68Manifold, J. A.: Report on a Trial of Plasmoquine and Quinine in the Treatment of Benign Tertian Malaria. J. Roy. Army M. Corps 56: 321, May; 410, June 1931.
69Kelleher, M. F. H., and Thompson, K.: Treatment of Malaria. Lancet 2: 217, 18 Aug. 1945.
70Dieuaide, R.: Clinical Malaria in Wartime. War Med. 7: 7-11, January 1945.


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by Dieuaide. In the Bulletin of the U.S. Army Medical Department,71 relapse rates are compared for various groups of patients treated in this country for acute attacks of vivax malaria of Pacific origin and followed for at least 90 days afterward. Of these, 176 patients were given quinacrine or totaquine alone, and 57 percent relapsed; 299 patients received 0.01 gm. Plasmochin base three times daily for 3 days after quinacrine or totaquine and quinacrine, and the combined relapse rate in all these Plasmochin groups was 56 percent. Here, again, is good evidence that Plasmochin for 3 days after other antimalarial therapy is not effective in influencing the relapse rate of Pacific vivax malaria. On the other hand, Gentzkow and Callender,72 in 1938, reported from Panama that this amount of Plasmochin (0.01 gm. three times a day for 3 days) in addition to 2.4 gm. of quinacrine, during 4 days, given to 128 patients resulted in a relapse rate of 9.4 percent in 6 months compared to 45.6 percent in 215 patients who received quinacrine alone. This report is based on analysis of patient malaria registers. From India, Bird73 reported 30.9 percent relapses in 152 patients treated with Plasmochin, 0.01 gm. three times a day for 5 days, following 5 to 7 days of quinacrine, and a relapse rate of 46.3 percent for 201 patients who received the same amount of Plasmochin after 7 days of quinine.

Summary-The evidence that has been cited indicates quite definitely that simultaneous quinine-Plasmochin treatment for 14 days or more of vivax malaria of Indian or Mediterranean origin resulted in a very significant reduction in relapse rates during periods of observation of from 2 to 6 months and that Plasmochin for 3 to 5 days after quinine, totaquine, or Atabrine is of no benefit in reducing relapses in vivax malaria of Pacific origin. In this connection, it should be borne in mind that the majority of relapses occur within a month after quinine or totaquine treatment and within 3 months after quinacrine or the 4-aminoquinoline drugs. Short-term courses of Plasmochin (3 to 5 days) are of doubtful value in reducing relapse rates in vivax malaria of Indian origin, and the reported beneficial effect of 3 days of Plasmochin after quinacrine in reducing relapses in vivax malaria of Panamanian origin remains unconfirmed.

Study at a specialty center

The following report from Moore General Hospital, a specialty center for tropical diseases, deals with the effect on subsequent relapse of simultaneous combined quinine-Plasmochin treatment for 14 days in vivax malaria of Pacific origin, which had not previously been studied.

71Treatment of Relapses of Vivax Malaria. Bull. U.S. Army M. Dept. No. 89, pp. 21-22, June 1945.
72Gentzkow, C. J., and Callender, G. R.: Malaria in the Panama Canal Department, United States Army. II. Results of Treatment With Quinine, Atabrine, and Plasmochin.  Am. J. Hyg. 28: 174-189, September 1938. 
73
Bird, W.: Atebrin and Plasmoquine in Treatment of Benign Tertian Malaria. J. Mal. Inst. India 5: 395, 1944.


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Material and methods.-The protocol described here was furnished by the Office of the Surgeon General. Seventy-two white patients with acute attacks of vivax malaria of Pacific origin having fever and positive smears were admitted to a special treatment and study ward. No attempt at selection of patients was made. All drugs were administered by a medical officer. On the first day, quinine sulfate, 1.0 gm., and Plasmochin naphthoate, 0.02 gm. (0.01 gm. base), were given together at 8-hour intervals. On days 2 to 14 inclusive, quinine sulfate, 0.65 gm., and Plasmochin naphthoate, 0.02 gm., were given together at 8-hour intervals. The total amount administered during the treatment period of 14 days was 28.35 gm. of quinine sulfate and 0.84 gm. of Plasmochin naphthoate. A control group of 75 patients with acute attacks of vivax malaria of Pacific origin were treated with a total of 28.35 gm. of quinine alone on the same schedule. Temperatures were recorded every 4 hours. Parasite counts were done twice daily until negative for 3 consecutive days. Hemoglobin, methemoglobin, and total white blood count determinations were made daily. (Hemoglobin and methemoglobin were determined colorimetrically as cyamethemoglobin.) Each patient was examined at least once daily by a medical officer, and special attention was paid to possible manifestations of Plasmochin toxicity. On the day after completion of treatment on the ward, the patients were transferred to a convalescent area for further observation. The duration of observation was until relapse or for a minimum of 120 days. During this interval, smears were examined twice weekly. In the event of parasitemia, temperature observations were made every 4 hours and parasite counts were done daily. A temperature of 100 F. or more by mouth in association with a positive smear was considered a clinical relapse.

Results-The cumulative clinical relapse rates during 120 days' observation after treatment of acute attacks with quinine, quinacrine, and combined quinine-Plasmochin are shown in chart 36. The total failures after treatment are summarized in table 76.

1. Quinine.-Seventy-five patients with acute attacks of vivax malaria of Pacific origin were treated with 28.35 gm. of quinine sulfate during 14 days. Sixty-two patients or 82.6 percent had a clinical relapse within 120 days. Five patients who did not relapse had, at one time or another during their period of observation, a positive smear without fever or symptoms. Thus, quinine failed to eradicate the infection in 67 or 89.3 percent of patients treated and observed for 120 days.

2. Quinacrine hydrochloride (Atabrine).-Sixty-nine patients with acute attacks of vivax malaria of Pacific origin were treated with 2.8 gm. of quinacrine during 7 days. Fifty-six patients or 81.2 percent had clinical relapses within 120 days after completion of treatment. An additional two patients who did not relapse had, at one time or another during their period of observation, positive smears without fever or symptoms. Thus, within


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CHART 36.-Relapse rates and intervals to relapse after treatment of acute attacks of vivax malaria of Pacific origin with various drugs

120 days following quinacrine, 84.1 percent of treated patients exhibited evidence that they were not cured of the infection.

3. Chloroquine diphosphate (SN 7,618).-Eighty-two patients with acute attacks of Pacific vivax malaria were treated with 1.5 to 2.0 gm. of SN 7,618 from 4 to 7 days. Sixty-two or 75.6 percent had a clinical relapse within 120 days after completion of treatment. Four additional patients developed asymptomatic parasitemia without clinical relapse during the 120-

TABLE 76.-Results of treatment in four groups of patients administered antimalarial drugs for acute attacks of vivax malaria of Pacific origin

1Clinical recurrence with fever, symptoms, and positive blood smear, observed within 120 days after treatment.
2Positive smear only, without fever or symptoms and not followed by clinical relapse during 120 days' observation after treatment.
3Clinical relapses plus parasitemic relapses during 120 days after treatment.


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day period of observation. In other words, a total of 66 patients or 80.5 percent of the whole number treated represent treatment failures in that they suffered clinical or parasitemic relapses while under observation after treatment with SN 7,618.

4. Combined quinine-Plasmochin.-Seventy-two white patients with acute attacks of vivax malaria of Pacific origin were treated with Plasmochin and quinine as described under "Material and Methods." Three clinical relapses occurred within 120 days after completion of treatment, a clinical relapse rate of 4.2 percent. Five additional patients showed parasitemia but had neither fever nor symptoms during the observation period. Thus, of 72 Pacific infections treated, there were altogether only 8 failures, making a total failure rate of 11.1 percent for the 120 days.

Toxicity

Clinical experience-Numerous references can be found in the literature dealing with toxic manifestations of Plasmochin of varying type and severity. Most frequently reported are gastrointestinal complaints, that is, mild to severe epigastric pain or soreness, anorexia, abdominal cramps, nausea, vomiting, and diarrhea; cyanosis; dyspnea and changes in pulse, in blood pressure and in electrocardiograms; changes in the blood varying from mild anemia to severe or fatal hemolytic crisis or agranulocytosis; vague muscular aches and pains and weakness; and symptoms referable to the central nervous system, principally headache, dizziness, "nervousness," psychosis, and coma. The incidence of severe toxic reactions varies from 1 to 10 percent in different series reported. The hemolytic reaction is the most serious manifestation of Plasmochin intoxication and may vary from mild progressive anemia to a sudden fatal hemolytic crisis associated with shock, severe anemia, jaundice, hemoglobinuria, and azotemia. This reaction may come on early after relatively small amounts of drug but also may occur at any time during the administration of Plasmochin. Weakness and dark urine are the most common symptoms at onset. During the acute episode the erythrocyte sedimentation rate accelerates; the white blood cell count and hemoglobin diminish. Race, diet, climate, and the prior administration of other drugs have all been suggested as factors that may be responsible for initiating a hemolytic reaction. Evidence will be reviewed regarding the possible relation of race to predisposition. The degree of methemoglobinemia in many individuals is probably related to the dose of drug. Gastrointestinal symptoms are most common during the fourth and fifth days of therapy and X-ray studies during this time have revealed gastric hyperperistalsis and intestinal spasm. There follows a brief summary of the incidence of toxic experiences reported in relatively large groups.

Manifold, in a 1931 report74 dealing with the results of treatment of vivax malaria in India with quinine, 1.25 gm., and Plasmochin, 0.04 gm.,

74See footnote 68, p. 581. 


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given together daily for 21 days, noted toxic symptoms or signs occurring in 21 percent of 1,298 British soldiers and in 10 percent of 1,915 Indians treated. Epigastric pain or other gastrointestinal symptoms were complaints in 15 percent of the British and in 8 percent of the Indian patients. Cyanosis was observed in 4 percent of the British cases but was not accurately determined in the Indians because of the color of their skin. Jaundice was observed in only three patients, and in one of these, an Indian, death followed as a result of a severe hemolytic reaction. In Manifold's opinion, the majority of the symptoms were mild. He also emphasized that, of 480 British patients personally treated, the full course of 21 days of Plasmochin was completed without interruption by all but 2 patients. He further stated that 98 to 99 percent of the patients in the entire series of more than 3,000 cases completed a full course of treatment.

West and Henderson,75 in 1944, reported an incidence of 2.85 percent Plasmochin toxicity in 846 patients treated for falciparum infections in Africa with quinine, 2.0 gm. daily for 3 days, quinacrine, 0.3 gm. daily for 5 days, no treatment for 2 days, then Plasmochin base, 0.03 gm. daily for 5 days. Twenty-two of the twenty-four patients with toxic signs had primary falciparum infections, and the other two had had malaria and had been treated with Plasmochin previously. Four patients were hospitalized after being given 0.66 gm. of Plasmochin base, and the mean total toxic dose was 0.119 gm. Jaundice was the most common finding and was observed in 20 patients, the mean icteric index being 27.6. Twenty patients had abdominal pain. Headache, weakness, and dizziness occurred in 16, 14, and 11 patients, respectively. Two patients were psychotic and one in coma. There was anemia in 19 patients, and in 1 the red cell count was 1.4 million per cubic millimeter, the average being 2.88 million per cubic millimeter. The white cell counts varied from 4.5 to 20.8 and averaged 10.2 thousand per cubic millimeter. All patients except one were ambulatory during the period of Plasmochin therapy. Unfortunately, the race of the patients or the ratio of black to white in the population sample reported is not stated in this paper.

The color of the skin is of particular interest, as Swantz and Bayliss76 in 1945 reported moderately severe hemolytic toxic reactions in nine Negroes who had received Plasmochin in the course of treatment for malaria. These reactions were encountered during a period in which approximately 3,000 cases of malaria were treated. The amount or duration of Plasmochin treatment is not stated. As to race, the authors say only that the majority of their malarial patients were white. The absence of a single hemolytic reaction in the whites treated and the occurrence of nine cases of severe intoxication in the Negroes suggest some predisposition to Plasmochin hemolytic reactions in Negroes. In studies summarized by Shannon, 6 hemolytic reactions

75West, J. B., and Henderson, A. B.: Plasmochin Intoxication. Bull. U.S. Army M. Dept. No. 82, pp. 87-99, November 1944.
76Swantz, H. E., and Bayliss, M.: Hemoglobinuria; Report of Ten Cases of Its Occurrence in Negroes During Convalescence From Malaria. War Med. 7: 104-107, February 1945.


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(5 Negroes and 1 Chinese) were observed among 71 pigmented patients, an incidence of 8.4 percent, but none in 35 white patients who received 0.03 gm. Plasmochin base for from 2 to 14 days. All reactions occurred during the third to fifth days of Plasmochin therapy and were characterized by weakness, dark urine, and icterus at onset.

Hardgrove and Applebaum,77 in 1945, reported from Panama an incidence of 10.13 percent hemolytic reactions in 4,361 laborers who were given a routine mass treatment for suppression of malaria, the treatment consisting of quinacrine, 0.1 gm. three times daily for 5 consecutive days, no medication for the next 2 days, and then Plasmochin base, 0.01 gm. three times daily, for 5 consecutive days. In 8.12 percent of the whole treated group, the reactions were sufficiently severe to require hospitalization. Three-fourths of these patients were admitted during a 48-hour period corresponding to the last day of Plasmochin treatment and the day following; only 21 toxic reactions occurred following less than 0.10 gm. of Plasmochin base. The principal complaints and findings were abdominal pain, dark urine, anorexia, jaundice, headache, nausea, and vomiting; abdominal tenderness, enlarged liver, pallor, cyanosis, low grade fever, hemoglobinuria, bilirubinemia, anemia, and leukocytosis. Treatment was essentially blood transfusion, intravenous glucose solution, and sodium bicarbonate by mouth. There were no deaths. It should be noted that in this series of patients a large proportion (not precisely stated) were not of the white race; also that the Plasmochin was administered to the men while they were working.

Kelleher and Thompson78 in their study of 660 British soldiers who were treated for acute attacks of vivax malaria with quinine, 2.0 gm., and Plasmochin base, 0.03 gm., daily for 10 consecutive days encountered practically no severe toxic manifestations. Of 295 patients personally treated by the authors, in only 3 was therapy interrupted because of toxicity. Other medical officers participating in the study, having less experience with Plasmochin, interrupted therapy in 2 to 4 percent of 365 subjects. No serious reactions were encountered.

It is evident from this brief survey of the literature that toxic experiences with Plasmochin vary considerably in their incidence and severity. Large groups of patients have been given 0.03 gm. of Plasmochin base for 10 to 21 days with practically no toxicity. On the other hand, serious hemolytic reactions have been reported when the drug was given for only 3 to 5 days. There is evidence that hemolytic reactions occur more frequently in patients who are not of the white race. Some investigators believe that toxic manifestations are more common in patients who have recently received quinacrine. Although it is true that the levels of Plasmochin in the plasma are very much higher in patients who have recently had quinacrine than in patients who have not, it has not been established that high plasma levels and

77Hardgrove, M., and Applebaum, I. L.: Plasmochin Toxicity; Analysis of 258 Cases. Ann. Int. Med. 25: 103-112, July 1946.
78See footnotes 69, p. 581.


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toxicity are related. It seems probable that taking Plasmochin while working may be a factor in producing serious reactions.

The writer (H.M.) and his coworkers administered Plasmochin naphthoate in doses of 0.02 gm. three times daily at 8-hour intervals for 14 days to 100 white patients. No major toxic manifestations were observed, and all patients were able to complete the full course of therapy.

Forty percent of the patients had some form of complaint referred to the gastrointestinal tract and probably related to Plasmochin. These symptoms usually began from the third to the fifth day and lasted from 1 to 7 days; they consisted principally of abdominal cramps or abdominal soreness which were rarely severe.

Cyanosis was observed on the 11th day of treatment in one patient who had a methemoglobin value of 12 percent. Ninety percent of the patients showed methemoglobinemia above normal values at some time during treatment with amounts ranging from 1.0 to 12 percent (average 2.3 percent) of total hemoglobin.

In 16 percent of the patients who were given Plasmochin for 14 days, there was a fall in total hemoglobin of from 11 to 20 percent during the second week of treatment which we considered related to the drug. An equal number of patients had an average fall in hemoglobin of 15.3 percent during the first 5 days. In the latter group, this fall in hemoglobin was apparently due to active malaria rather than to Plasmochin therapy since it occurred in the first few days of the acute attack and reversed itself with continued treatment. Severe anemia did not occur, and no hemolytic crisis was observed.

The effect of Plasmochin on the white blood cell count was to produce leukocytosis in a significant number of men (15 percent with counts above 10,000 per cubic millimeter) during the second week of treatment and leukopenia (24 percent with counts below 5,000 per cubic millimeter) during the first week after discontinuance of the drug. Subsequent counts 2 weeks after treatment were all normal.

In our experience, the toxic manifestations related to the administration of Plasmochin were not severe or serious and should not detract from the value of the drug if proper care is taken in recognizing potentially serious signs of toxicity.

Recommendations for therapeutic use-It is suggested that patients given Plasmochin as described in this chapter be hospitalized during treatment and observed frequently to recognize early severe hemolysis, should it occur. Treatment with Plasmochin should be limited to white patients. Hemoglobin determinations should be done daily and complete blood counts at least twice a week. Cyanosis alone is not an indication for discontinuance of therapy. A fall in total hemoglobin of more than 20 percent in any one day should be regarded with suspicion; if followed by a further decline in the amount of total hemoglobin on the next day, Plasmochin treatment should stop. One cannot anticipate sudden hemolysis by any laboratory method,


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but symptoms of severe weakness and dark urine during the first 5 days of therapy should be investigated with this possibility in mind. Fluids, blood, and alkalies by vein are indicated if a severe reaction should occur. Abdominal cramps occur most frequently during the first week of treatment and if severe may be controlled with atropine. The usual symptoms of cinchonism, namely, tinnitus, fullness in the head and ears, and headache, were encountered in varying severity in the first week of treatment in the majority of patients. These symptoms gradually subsided in the second week and caused no interruption of therapy. During the first 2 to 5 days of the acute attack of malaria, most patients should remain in bed. For the remainder of the 2-week period of treatment in the hospital, the patients may be ambulant on the ward but should not be permitted vigorous exercise nor be given overnight passes. Each dose of drug must be personally administered by a nurse or physician, and each patient should be seen at least twice daily. Patients with anemia, severely malnourished, or in poor physical condition should not be treated with Plasmochin.

Discussion

The clinical relapse rate of only 4 percent and a total failure of 11.1 percent following combined treatment with quinine and Plasmochin is very striking. In our experience, the clinical relapse in 10 groups of at least 50 patients each has varied from 65 to 85 percent, with total failure rates after treatment of from 75 to 90 percent for all groups except the group treated with quinine-Plasmochin as here reported.

Analysis of more than 1,000 attacks of vivax malaria treated and observed at Moore General Hospital for 120 days indicated that within this period of observation the relapse rate for any given attack is not significantly influenced by the number of previous attacks, by the age of the disease (table 76), or by the amount or duration of treatment with quinine or quinacrine. It is unlikely that these factors can account for the wide discrepancy in the observed results. One must also consider what the probability may be of late relapses occurring in the quinine-Plasmochin group after the 120 days' period of observation. The median interval to clinical relapse following treatment with quinine or totaquine is 24 days and following quinacrine or 4-aminoquinoline drugs, 50 to 65 days. Within 120 days, 80 to 90 percent of all patients treated for an acute attack of vivax malaria of Pacific origin with currently used antimalarial drugs will have interval parasitemia without fever or symptoms or will actually relapse clinically. We know that a relatively small percentage of failures do occur after 120 days. It is unlikely that absolutely no definitive cures follow treatment with quinine or quinacrine, but even if this were so, the maximum number of failures that could possibly occur after 120 days' observation would be only 10 to 20 percent of treated patients. The median interval to failure (parasitemic and clinical) in the relapses that actually were observed in the quinine-Plasmochin group was 34 days compared to 36 days for the quinine controls. In other words, when


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quinine-Plasmochin failed it did so in the same interval after treatment as did quinine alone. Subsequently, we observed 20 percent of the Plasmochin group for at least 180 days after treatment and no failures after 120 days had occurred. Unless Plasmochin alters the biology of vivax malaria in man so that very late failures will occur in the majority of treated patients, it is our opinion that the freedom from parasitemia or clinical relapse for 120 days in 90 percent of our treated patients represents definitive cure for at least 80 percent of men so treated.

Analysis of our Plasmochin relapses gives us no clue to a possible explanation for failure. The average mean plasma levels of quinine and Plasmochin are in the same order and range in the failures as in the whole group treated as well as for the patients in whom 120-day cures were observed. There was one failure in nine delayed primary attacks treated. As regards the average age of the disease and the average number of previous attacks, the other seven failures were comparable to the patients in whom treatment was successful.

Clinical use-Four-month cures in 90 percent of patients treated with combined quinine-Plasmochin raised the question of the general application of this form of treatment for vivax malaria. In infections of Mediterranean origin, the relatively low clinical relapse rate of 30 percent within 120 days for vivax malaria following treatment with quinacrine or quinine makes it questionable whether routine Plasmochin treatment is indicated in such infections, especially in the second year of the disease. Certain individuals, however, with vivax malaria of Mediterranean origin relapse frequently and at short intervals after treatment during the first year of the disease particularly if quinine is used to terminate the acute attack. In these cases, combined quinine-Plasmochin treatment should be considered.

Since 120-day failure rates after treatment of attacks of Pacific vivax malaria may be as high as 90 percent, more serious consideration should be given to the use of combined quinine-Plasmochin in this type of infection. Even though there is only a 10 to 20 percent chance that a patient treated with quinine or quinacrine for his first attack will have no subsequent attack in 120 days, it seems worthwhile to take this chance for that attack and possibly for the next one or two relapses. However, the occurrence of repeated attacks, at short intervals, for example, 3 to 6 attacks during the first 6 months of the disease or repeated attacks later in the disease, is in our opinion an indication for the use of combined quinine-Plasmochin therapy. The co-existence of other diseases precluding the use of quinacrine therapeutically or for suppression (quinacrine sensitivity and/or exfoliative or eczematoid dermatitis or atypical lichen planus) is another indication for the use of combined quinine-Plasmochin. Likewise, patients who relapse frequently at intervals of a month or less after quinine and who cannot take quinacrine can be treated with Plasmochin, as outlined. Finally, patients whose convalescence from other diseases is interrupted or delayed by repeated attacks


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of malaria should be considered candidates for combined quinine-Plasmochin therapy. Each case must be considered individually and the probability of cure weighed against potential toxicity and a 2 weeks' course of hospital treatment with Plasmochin, compared with a short, safe course of treatment with other antimalarial drugs and the high possibility of failure.

Appreciating the potential dangers of Plasmochin, one is nevertheless impressed by the complete absence of severe or serious toxicity in a series of 100 consecutive white patients who were given 0.06 gm. Plasmochin naphthoate daily for 14 days. The fact that the patients were all white, closely observed in the hospital, and in good physical condition may be factors in the absence of toxicity.

Further study-Following completion of the study just described, 30 additional white patients with acute attacks of vivax malaria of Pacific origin had, in addition to quinine, quinacrine, or SN 7,618, received Plasmochin for 14 days. Information was now available on relapse rates during 120 to 180 days' observation after treatment for more than 100 cases of vivax malaria. The observed relapse rate for the group was 4 percent and the total failure rate less than 10 percent. There can be little question about the curative value of Plasmochin.

It is interesting that, in a group of 10 men who received Plasmochin for 14 days after 2.2 gm. of quinacrine had been given to terminate the attack, only one relapse occurred during 120 to 180 days' subsequent observation. No relapse occurred in a similar period of observation in another 10 men who received, during the first 4 days of treatment with Plasmochin, a total of 1.4 gm. of SN 7,618 in addition to the Plasmochin, which was given for a total of 14 days. It seems that successful treatment with Plasmochin may be accomplished after the acute attack is terminated with quinacrine or SN 7,618, or by giving either of these drugs simultaneously with Plasmochin for a few days until the acute attack has been terminated and then continuing Plasmochin until it has been given for 14 consecutive days.

It is noteworthy that of the 100 cases successfully treated with Plasmochin there were 20 patients with primary attacks and 19 with only one prior attack. There were only 2 failures in this group of 39 men, or a failure rate of 5 percent. The severity of infection acquired naturally may vary considerably, but all evidence suggests that the age of the disease or severity of infection is of secondary importance in determining the end results of Plasmochin therapy. Likewise, no correlation has been found between Plasmochin plasma levels and success or failure of treatment. On the other hand, total dose and duration of treatment appear to be crucial factors. For example, in a group of 10 men who received combined quinine-Plasmochin treatment for only 10 instead of 14 days, 6 relapses occurred.79 Similar failures were reported in treatment of primary attacks or relapses if the total dose of Plasmochin was 0.42 instead of 0.84 gm. during 14 days.

79Most, H.: Unpublished data.


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Summary

The clinical studies on the effect of Plasmochin in definitively terminating vivax infections are of the utmost importance in the chemotherapy of malaria. As a result of these carefully controlled experiments, Plasmochin or similar drugs were established with a definite place in the management of relapsing vivax malaria. The original observation by James80 that Plasmochin given in adequate amounts before, during, and after sporozoite infections resulted in cure of vivax malaria has been clinically applied. Similar results with domestic and foreign strains of P. vivax in protective and therapeutic tests have been reported in the United States. Treatment of primary attacks or relapses resulted in cures in the great majority of cases in which total doses of Plasmochin of 0.84 gm. were given with quinine or other drugs for 14 days.81

Extension of these studies has been made with other 8-aminoquinoline compounds. At least one of these, SN 13,276 or pentaquine, has great promise. No clinical studies with this drug were made in the U.S. Army during World War II. However, it has been shown by civilian and Federal research agencies that it will produce a greater number of cures than Plasmochin in primary attacks and relapses of vivax infections transmitted by mosquitoes as well as in protective tests. It has also been shown that it may be less toxic.

Summary of Studies

Protective tests and clinical trials conclusively demonstrated the curative properties of this class of compounds. A reevaluation of Plasmochin resulted in the demonstration that if this drug is administered with quinine or other drugs for 14 days vivax malaria will be cured in 80 to 90 percent of naturally acquired clinical disease. In contrast, relapse will be forestalled in only 10 to 20 percent of vivax infections after treatment with quinine, quinacrine, or the 4-aminoquinolines. The feasibility and safety of administering 0.84 gm. of Plasmochin to white patients was shown, with only minor toxicity occurring. Plasmochin, which has had its "ups and downs" in the story of the treatment of malaria, was shown to have a definite and important position in the management of relapsing vivax malaria. As a result of detailed studies of the 8-aminoquinoline compounds, new members of this group have been found which may be so superior to Plasmochin as to end the search for a curative antimalarial drug.

SUMMARY

The magnitude of the malaria problem during World War II can be appreciated only if it is realized that the war was fought in areas where the disease is endemic and that about a half million cases developed in the U.S.

80James, S. P., Nichol, W. D., and Shute, P. G.: On the Prevention of Malaria With Plasmoquine. Lancet 2: 341-342, 15 Aug. 1931.
81See footnote 64, p. 579.


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Army. At the beginning of the war, there was great anxiety with regard to the loss of our sources of quinine, and there was some question concerning the efficacy of quinacrine as a suppressive and therapeutic agent. Our scientific resources were beautifully organized in a search for better antimalarial drugs. Fundamental studies and a rational approach to the problem led to a clear understanding of the optimum methods of using quinine and quinacrine. Newly developed methods made it possible to compare the relative efficiency of various drugs. It was shown that certain sulfonamides could be substituted in extreme emergencies as suppressive agents. Heavy metals on the whole offered little promise. Antibiotics were of no value.

Quinacrine was shown to be superior to quinine for all purposes except possibly for the treatment of fulminant infections with P. falciparum. The toxicity of quinacrine was extensively studied; hitherto undescribed reactions, in particular the eczematoid-lichen-planus-dermatitis complex, and aplastic anemia were encountered in a small percentage of cases. In proper dosage, quinacrine was more effective than quinine in terminating acute attacks and in curing those caused by P. falciparum, while the proper use of quinacrine for suppression made possible successful military campaigns in highly malarious areas. Mortality from malaria during World War II was negligible principally because of effective treatment and suppression of clinical malaria.

In the search for new drugs, the 4- and 8-aminoquinolines were widely studied. Several (SN 6,911 and SN 8,137) were as effective as quinacrine and if necessary might have been substituted for it. In addition, one was found (SN 7,618 or chloroquine) that was superior to quinacrine. It does not discolor the skin; it could apparently be given with safety over a long time and would produce satisfactory suppression by single weekly doses. These drugs also cure falciparum infections. No studies were available on their value in fulminating falciparum infections in comparison with quinine or quinacrine.

Finally, the curative properties of the 8-aminoquinoline compounds were demonstrated. Plasmochin was reestablished as a drug of great value in the treatment of relapsing vivax malaria in conjunction with quinine, and new compounds were found (SN 13,276 or pentaquine) which may have fulfilled the search for a generally curative antimalarial agent. The final step in progress to the ideal therapeutic will be an agent that is truly chemoprophylactic. Such a drug may be found, which will be safe when taken over long periods and will completely prevent the development of infection.

This is how the matter stood when World War II ended. The momentum of these studies carried over into investigations continued during the postwar years 1946-54. These investigations were for the most part under the auspices of the U.S. Army. A note is appended on this work, as it ties together the whole and brings it to more sharply defined conclusions. This addendum


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on postwar research is drawn from a review prepared by Dr. L. H. Schmidt and Dr. G. Robert Coatney.82

Postwar Research

At the close of hostilities, it was evident that much work remained to be done with intent (1) to evaluate known but inadequately assessed suppressive and therapeutic agents and (2) to develop new curative drugs. Many investigators who during the war had taken part in the research programs of the Office of Scientific Research and Development (OSRD) retained their interest in the chemotherapy of malaria. It seemed to them that this unfinished business could best be completed within a similar pattern of cooperative effort.

Accordingly, the fruitful period from 1946 to 1954, inclusive, saw investigations in large part conducted with the active participation and support of the armed services. A Malaria Study Section, under the U.S. Public Health Service, recommended grants-in-aid to interested scientific workers at various institutions. They, together with parasitologists and clinical investigators in the Section on Chemotherapy, Laboratory of Tropical Diseases, National Institutes of Health, agreed to coordinate their activities to achieve specified objectives. A joint group known as Investigators in Malaria Chemotherapy met frequently from October 1946 through 1948 to assess progress and plan new activities.

Investigations under OSRD had established the value of quinacrine. Of the compounds that gave promise in preliminary tests or of having even superior qualities, only one, chloroquine, had been tested sufficiently to be recommended for general use. Two other compounds, amodiaquin and oxychloroquine, belonging to the same chemical group, the 4-aminoquinolines, seemed to merit further trial, as did the 4-quinoline-methanols and a small number of naphthoquinones. In addition, there were the biguanides, particularly chlorguanide, made available to OSRD investigators through the scientific liaison between Great Britain and the United States.

It had been recognized also, during the latter years of the wartime studies, that certain prewar work by the British had shown that the old German drug pamaquine (Plasmochin) possessed a property not common to other antimalarial drugs; namely, its ability to cure naturally acquired vivax malaria. This recognition led to confirmatory observations and subsequently to a large program involving synthesis, pharmacological study, and clinical evaluation of the 8-aminoquinolines, a program which dominated the last year of OSRD activities in this field. At the end of the war, this effort had led to the development of at least one compound, pentaquine (SN 13,276), believed to be superior to pamaquine.

82Schmidt, L. H., and Coatney, G. R.: Review of Investigations in Malaria Chemotherapy (U.S.A.) 1946 to 1954. Am. J. Trop. Med. 4: 208-216, March 1955.


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In the first of the cooperative postwar studies, the naphthoquinones were found to have only a low level of therapeutic effectiveness and gave no evidence, in man or monkey, of prophylactic or curative properties. Of the 4-quinoline-methanols, three compounds were shown to possess no significant advantages over quinine in the treatment of vivax malaria. The fourth produced phenomenal lengthening of the relapse interval, but this was associated with the development of photosensitivity. Accordingly, work on all of these compounds was abandoned. In the 4-aminoquinoline group, continued investigation on the long-term suppressive activity of chloroquine, and on the short-term suppressive and therapeutic properties of amodiaquin, showed that these drugs possess similarly high therapeutic and suppressive activity. The effectiveness and tolerability of chloroquine given intramuscularly, and its effectiveness in single doses given orally, were amply demonstrated.

Chlorguanide, the biguanide that had shown considerable promise in preliminary clinical evaluation by British, Australian, and OSRD investigators, was now thoroughly studied in man and experimental animals. Long-term administration was found to be safe. In the body, the drug was degraded extensively to products that, like the parent drug, exhibited activity against simian malaria. Although, as shown by British investigators, one compound was formed that was more active than the parent compound against avian malaria, subsequent work by other British investigators showed that this metabolic product was no more active than the parent drug against infections with P. falciparum. In therapeutic and suppressive studies, chlorguanide exhibited a high degree of activity against infections with P. vivax, but it was definitely slower than chloroquine in reducing fever and parasitemia. It was further shown that each of the species of avian, simian, and human plasmodia studied acquired a high order of resistance to the drug when exposed to suboptimal doses and that the resistant characteristic of the simian plasmodium could be transmitted unaltered through the mosquito. When produced in sporozite-induced infections, resistance was a property of the erythrocytic parasites only. Infections with chlorguanide-resistant strains responded normally to drugs such as quinine, quinacrine, and the 4-aminoquinolines. Field study in Guatemala confirmed the superiority of chloroquine for suppression in a systematic comparison with chlorguanide.

These various studies had thus established the therapeutic potentialities of both chloroquine and amodiaquin and demonstrated that either drug was superior to chlorguanide in the general management of malaria in man. The work of consolidation was in general complete.

The major new effort of the Investigators in Malaria Chemotherapy was directed toward development of a generally useful drug that would not merely suppress but would cure the relapsing malaria caused by P. vivax. This attempt, centered about work on the 8-aminoquinolines, during 1946 and 1947 followed the pattern of the last year of the OSRD program. This involved synthesis of various congeners of pamaquine (Plasmochin), testing for tox-


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icity in monkeys, and finally testing of compounds free of neuronal toxicity against vivax infections in human volunteers. In addition, efforts were made to define more precisely the activity of pentaquine and the more effective ways of using it.

In 1948, this pattern of work was changed as the result of a demonstration by Schmidt and his colleagues at the Christ Hospital Institute of Medical Research, Cincinnati, Ohio. They showed that infections with Plasmodium cynomolgi in the rhesus monkey were the biological and chemotherapeutic counterparts of infections in man with Southwest Pacific strains of P. vivax, with essentially complete parallelism in response both to qualitative and to quantitative aspects of drug activity. For the first time, it was possible to carry out toxicological and, particularly, therapeutic studies in an experimental animal with reasonable expectation that the results could be translated in terms of malaria in man.

Collaborating groups of chemists at Columbia University, New York, N.Y., University of Maryland, College Park, Md., and University of Notre Dame, Notre Dame, Ind., synthesized 42 new 8-aminoquinoline derivatives and remade older analogs in quantities sufficient for simian and human studies. Toxicological and curative therapeutic studies were carried out on all of these compounds in monkeys at the Christ Hospital Institute, and 18 of the compounds were selected for human trial at the University of Chicago, Chicago, Ill. Both in man and in monkey, four compounds emerged with properties superior to pamaquine. These were pentaquine and isopentaquine, which had been developed in 1946 and 1947, respectively, primaquine (SN 13,272), and SN 3,883. The last two compounds, with terminal primary amino groups on the side chain, had been prepared during the OSRD program but were subjected to study in man only after investigations at the Christ Hospital Institute had focused attention upon the high tolerability of this class of compounds and their unusual activity against the early and late exo-erythrocytic stages of P. cynomolgi.

Between 1948 and 1950, considerable study was also given to the mechanisms for enhancing the effectiveness of known agents. Two observations that proved of practical significance were made at the Christ Hospital Institute and later confirmed in principle in the human subject at the University of Chicago. These observations were (1) quinine had no specific enhancing effect on the curative activities of 8-aminoquinolines such as pentaquine, isopentaquine, and primaquine, and (2) that these drugs could cure and in some cases prevent malaria infections when given alone. It followed that the sole contribution of quinine was the control of erythrocytic infection. This contribution explains the therapeutic effectiveness of Plasmochin combined with quinine; it could be made as well by chloroquine or any other schizonticidal drug, or could be dispensed with if the 8-aminoquinoline were administered, in established infections, in the interval between relapses. This finding formed the basis for the "interim primaquine" regimens which allegedly have


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been responsible for the reduced incidence of malaria among troops returning from Korea in 1952 and 1953.

Late in 1950, it was decided to concentrate the cooperative studies upon the relative merits and best use of the four compounds that seemed most promising, pentaquine, isopentaquine, primaquine, and SN 3,883. Evaluation of these drugs in curing established infections with P. vivax in volunteers was in part made the responsibility of a group of investigators headed by Dr. Alf S. Alving at the University of Chicago. A second clinical testing facility was established at the U.S. Penitentiary, Atlanta, Ga., under the direction of Dr. Coatney.

In the meantime, the appearance of numerous cases of acute malaria among military personnel returning from Korea demanded more immediate solutions. At a meeting called by The Surgeon General, Department of the Army, on 3 July 1951, it was decided to focus attention upon primaquine and particularly to investigate (1) its effectiveness in eradicating established infections in returnees from Korea and (2) the feasibility of administering 15 mg. daily for 14 days to all servicemen returning from Korea by ship.

The overall safety of this dosage schedule for military men on full duty was demonstrated in a preliminary investigation, involving 1,000 U.S. Army personnel, carried out at Fort Benning, Ga., and Fort Knox, Ky. Beginning on 18 September 1951 with a group of servicemen returning by ship from Korea, the administration of 15 mg. of primaquine daily for 14 days was adopted as a general procedure pending more precise data from the controlled studies underway in the United States. Collateral studies at the University of Chicago showed that daily doses of 30 mg. of primaquine were tolerated by Caucasians; in Negroes, such doses evoked intravascular hemolysis in 5 percent.

Data from the controlled studies on prisoner volunteers, available in January 1952, showed the superiority of primaquine over pentaquine, isopentaquine, and SN 3,833 as a curative drug. The results obtained in active infections with P. vivax in returnees from Korea showed the high order of curative effectiveness of primaquine and its superiority over pamaquine (Plasmochin). The effectiveness of interim treatment with primaquine was demonstrated in selected returnees. This composite information, together with toxicological data obtained by study of prisoner volunteers, provided a solid basis for the adoption of interim treatment with primaquine for the cure of vivax malaria of Korean origin. This procedure was eventually applied to all military personnel returning by ship from Korea and has been associated with the virtual elimination of malaria among them.

Late in 1950, interest was aroused in a new type of antimalarial drug which had been produced in the Wellcome Research Laboratories, New York, as a by-product of investigations on purines and pyrimidines as carcinolytic agents. Attention centered on pyrimethamine (2, 4-diamino-5-p-chlorophenyl-6-ethylpyrimidine, Daraprim). Extensive studies were carried out on its


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pharmacology in man and lower animals, on its activity against avian and simian malarias, and against infections with P. vivax and P. falciparum. Therapeutic studies in both lower animals and man showed that the compound had higher activity against erythrocytic parasites than any known antimalarial drug. It was slower, however, than chloroquine in controlling active simian and human infections. It was active against the exo-erythrocytic stages of all species of malarial parasites studied. It was able to effect suppressive cure in a high proportion of infections with P. vivax. Resistance to pyrimethamine developed rapidly during inadequate treatment of erythrocytic infections with avian, simian, and human plasmodia. In cynomolgi and vivax malarias, the resistance characteristic could be transferred unchanged through the mosquito. Pharmacological studies in the monkey demonstrated that repeated administration of pyrimethamine produced significant deleterious changes in the bone marrow, kidney, and adrenal cortex. Tolerability studies in man attested to the safety of the currently recommended doses of pyrimethamine but showed that, at a sevenfold increase in dosage, changes occurred in the bone marrow similar to those exhibited by the monkey.

The capacity of pyrimethamine to function as a suppressive cure strongly recommended its use by U.S. armed services. On the other hand, its potential for inducing resistant strains and its slowness of action in treatment of acute attacks were disadvantages not possessed by chloroquine.

In conclusion, one sees that during the period from 1946 to 1954, inclusive, there were marked developments in the chemotherapy of malaria. The position of chloroquine and amodiaquin in the suppression and treatment of vivax and falciparum malarias and in the cure of the latter was established firmly. The usefulness and limitations of chlorguanide were defined with reasonable certainty. A generally useful drug for the cure of relapsing infections with P. vivax was developed in primaquine, and the value of this agent was proved in both laboratory and field investigations. Finally, a new compound, pyrimethamine, possessing interesting possibilities as a suppressive antimalarial drug, was introduced. The ultimate significance of these developments for worldwide control of malaria remains to be appraised. It seems likely, however, that satisfactory measures are now at hand for suppression, treatment, and cure of all human malarias. This remarkably favorable position of malaria therapy is in marked contrast to the uncertainty of the pre-World War II period. It is a tribute to all who took part in the OSRD and postwar malaria researches.

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