Chapter 14
Malaria: Chemotherapy
Brigadier General Andre J. Ognibene, MC, USA, and Colonel Nicholas F. Conte, MC, USA (Ret)
INITIAL EXPERIENCES, 1960-65
As the 1960`s commenced, the relaxed satisfaction of malaria researchers was shattered by rapidly increasing reports from various parts of the world of the emergence of chloroquine-resistant strains of Plasmodium falciparum. Moore and Lanier (1961) reported the first cases of chloroquine-resistant falciparum malaria in two American geophysicists working in Colombia, South America. Both received several courses of chloroquine and were finally cured with a 10-day course of quinine therapy. The strain from one patient, who had acquired his infection in the Magdalena Valley, was used in a study of volunteers with neurosyphilis which demonstrated unequivocally that it was indeed chloroquine-resistant (Young and Moore 1961). Similar reports followed about strains from Thailand (Young et al. 1963), Cambodia and Malaya (now West Malaysia) (Contacos, Lunn, and Coatney 1963; Montgomery and Eyles 1963), and Brazil (Box, Box, and Young 1963). Sandosham, Eyles, and Montgomery (1964) reported on an outbreak of drug-resistant malaria in north Malaya near the Thai border among Australian troops on daily proguanil prophylaxis. Contacos, Lunn, and Coatney (1963) compared the sensitivity of two Cambodian, three Malayan, one Colombian, and one Thai strain of P. falciparum (table 46). The susceptibility of all strains to quinine was striking.
The first documented case of chloroquine-resistant falciparum malaria in U.S. military personnel was that of a 34-year-old marine who acquired the disease while stationed in Vietnam (Powell et al. 1964). Captain Sn. experienced his first acute clinical attack in late August 1962, and on 27 August asexual erythrocytic forms of P. falciparum were found in his blood smears. He was then given three courses of chloroquine base, in the standard regimen (1,500 mg over a period of 3 days) or in larger doses (2,700 mg over 7 days). These courses were administered three times: during the last week of August, the third week of September, and the first week of October. Each resulted in a temporary abatement of symptoms and overt parasitemia, but recrudescence (fever and positive smears) occurred 2 to 3 weeks after both of the first two courses. During the second and third weeks of November 1962, after transfer to the U.S. Naval Hospital, Great Lakes, Ill., the patient received 1,935 mg of quinine sulfate daily
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for 10 days and a concurrent course of 50 mg of pyrimethamine daily for 3 days, resulting in radical cure. A summary of the patient`s clinical record * follows:
The patient is a 34-year-old white male Marine Captain who was first admitted to the 8th Field Hospital on 27 August 1962. For approximately 5 days prior to admission he had noted fever, myalgia, arthralgia and recurrent, shaking chills recurring at about 48-hour intervals. System review was negative otherwise except for severe retro-orbital headaches.
Past History: Was significant in that the patient had a previous episode of malaria eight years previously while in Korea.
Physical Examination: Well developed, thin white male who appeared acutely and seriously ill-perspiring profusely. BP 108/60. P 100/min. T 102F. R 16/m. Skin negative. Lymph nodes negative. ENT normal. Lungs clear to P&A. Heart sinus tachycardia, no murmurs, no cardiomegaly. Abdomen normal except for spleen, palpable 2 cm on deep inspiration, firm and nontender.
Course in Hospital. Blood smear on admission was positive for malaria, judged to be falciparum on the basis of double ring forms in the erythrocytes; no more mature forms were seen (this Dx was confirmed by the Malaria Control Commission Nha Trang, Vietnam). Routine blood count showed wbc 6100 with normal differential, hematocrit 44; urinalysis and chest X-ray normal. Patient treated with chloroquine 0.6 gm (base) stat followed by 0.3 gm in 6 hours then 0.3 gm daily x 3 and primaquine 15 mg per day for 14 days. He was afebrile in 96 hours, remained asymptomatic and was discharged on 6 Sept. to convalescent leave then duty.
Second Admission: Patient was readmitted to the hospital on 20 September. Several days prior to admission he had watery diarrhea lasting 1 day then had recurrence of myalgia and fever but without shaking chills until the day before admission.
Physical Examination: Was unchanged except that the patient was quite pale; spleen was palpable 5 cm below the costal margin and was tender. Temperature 105F. Smear was again positive for P. falciparum. Because of the anemia which was felt to be hemolytic in nature, a direct Heinz body preparation was made but was negative (patient had been given a course of primaquine on first admission). The anemia was judged secondary to the hemolytic effect of the disease. No facilities were available to further characterize the anemia. He was given a repeat course of chloroquine with maintenance for 6 days. On admission the hematocrit was 29 and gradually rose to 35 while in the hospital. He has had a leukopenia or low normal wbc throughout. Liver battery showed bilirubin 0.3 mg % total; SGPT 6 units; BSP retention 3% in 45 min. Patient was afebrile for 11 days then had temperature to 101F. This was felt due to an acute prostatitis for which Rx was begun. 48 hours later he had temperature of 104F, a shaking chill and again had a positive smear. A third course of chloroquine was given.
This patient has had three separate episodes of P. falciparum within a 6-week period. The course suggests that this is chloroquine-resistant P. falciparum. In keeping with the suggestion of
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* Maj. O`Neill Barrett, Jr., MC: Narrative summary, clinical record of Captain Sn., 8th Field Hospital, Nha Trang, 1962.
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Col. William Tigertt, Office of the Surgeon General, Research and Development Command, this patient is to be transferred to Great Lakes Naval Hospital for further study and treatment by Dr. Alving and his group.?
The therapeutic pendulum had swung from quinine to chloroquine and now back to quinine. Infected blood inoculated into volunteers was used to establish refractoriness to several synthetic antimalarials and support the efficacy of the quinine and pyrimethamine combination. The strain was designated Vietnam (Sn.) (Powell et al. 1964).
Legters et al. (1965) presented a detailed report of three soldiers who acquired falciparum malaria in Vietnam and required several courses of chloroquine and quinine before a radical cure was achieved. One of these patients provided the resistant strain designated Vietnam (CV). Later, this strain was used in volunteer clinical studies which demonstrated the ineffectiveness of chloroquine and pyrimethamine against it and provided additional evidence of variability among different strains of chloroquine-resistant P. falciparum in their response to pyrimethamine (Eppes et al. 1966). Map 9 shows the locations in Southeast Asia where drug-resistant malaria was contracted.
Thus, it was quite clear, particularly to those in research positions, that the research and development problem which would require the highest priority was drug-resistant malaria. At U.S. Army Medical Research and Development Command Headquarters on 6 August 1965, members of The Surgeon General`s staff convened to assess the problem. They recommended that the Army Vice Chief of Staff, Gen. Creighton W. Abrams, Jr., and the MACV (Military Assistance Command, Vietnam) surgeon, Col. (later Maj. Gen.) Spurgeon H. Neel, Jr., MC, be advised of the seriousness of the situation. The consensus at that time was to retain the standard 3-day chloroquine treatment during the acute attack of malaria while research progressed. Furthermore, it was believed that the weekly C-P (chloroquine-primaquine) tablet should be the routine method of chemoprophylaxis and should also be given following therapy for clinical malaria in preference to the 14-day primaquine regimen. The potential problem with G6PD (glucose-6-phosphate dehydrogenase) deficiency was recognized, but the efficacy of primaquine in eradicating the tissue phase was considered overriding. The Surgeon General, Lt. Gen. Leonard D. Heaton (1965) dispatched a memorandum to General Abrams following the meeting, emphasizing the impact of malaria on the effectiveness of troops in Southeast Asia, the essential elements of good malaria discipline, drug prophylaxis, and the necessity for indoctrination of all officers. Medical officers attending the Medical Field Service School were to receive additional instruction about malaria.
The malaria attack rate was low before June 1965 when there were few military personnel in Vietnam. Only 800 U.S. Army personnel were present in 1960, principally military advisers and Special Forces personnel; the number had risen to slightly less than 15,000 in 1964. By the end of 1965, however, the United States had fielded a significant military force in South Vietnam, numbering 184,300, of which almost 117,000 were U.S. Army troops (MACV-MP).
As contact with the opposing forces increased, the malaria attack rate rose precipitously. Early data grossly understated the problem because of the dif-
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ficulties of reporting cases and the large number of patients evacuated out of country. By the end of 1965, 1,972 cases of malaria were recorded, most of which occurred during the last 3 months of the year; 16 cases were fatal (Neel 1973, pp.38-39). The incidence in some combat units, such as the 1st Cavalry Division (Airmobile [AM] ), approached 350 per 1,000 per year, in contrast to 22 per 1,000 per year in combat support units.* This high incidence in combat units was directly related to military operations in the Central Highlands where malaria was known to be highly endemic and troops were in close contact with Vietcong and North Vietnamese elements.???
It was difficult to assess the early clinical experience because of the multiplicity of drug regimens, incomplete medical records, and hasty evacuation of patients from Vietnam. Sheehy and Reba (1967) reviewed the initial experience in several Army hospitals in the country. They noted that up to 50 percent of personnel participating in operations in the Ia Drang and Vinh Thanh valleys of central Vietnam developed clinical malaria, and about 5 percent developed an asymptomatic parasitemia which was ultimately cleared by chemoprophylaxis with chloroquine and quinine. Vivax infections continued to be effectively suppressed with chloroquine-quinine treatment. However, virtually all the clinical infections were caused by P. falciparum and most were resistant to chloroquine therapy. Seventy percent of the P. falciparum infections in nonimmune patients were only partially responsive to chloroquine therapy, with early recrudescences 1 to 4 weeks later; 10 to 20 percent of these cases were refractory to a second course of treatment. Quinine was more reliable in terminating the acute attack, although a dosage of 650 mg every 8 hours for 14 days proved inadequate to effect a radical cure, and there was a 70 to 90 percent rate of recrudescence within a month. Pyrimethamine used alone was no better; in small groups treated with a dose of about 25 mg every 8 hours for 3 days, early recrudescences ranged from 15 to 40 percent. With this background, five drug regimens were systematically evaluated in late 1965, as outlined in table 47. Regimen III, quinine 14 days with 3-day pyrimethamine, was the best of the group with a radical cure effected in 93 percent (125 of 135 patients). Nine patients had recrudescences and only one was refractory to subsequent therapy. Three of the 135 patients treated with quinine and pyrimethamine, an antifolic acid compound, developed megaloblastic anemia (which was later responsive to folic acid administration).
Orbison (1966) reported a similar experience with drug-refractory falciparum malaria at Tripler General Hospital in Honolulu when many patients were being evacuated to Hawaii from Vietnam. Within 2 months, October to December 1965, 286 patients were admitted. Altogether they had received 11 individual or combined drug treatment schedules in Vietnam. The early arrivals at Tripler were placed on the standard 3-day chloroquine regimen followed by the weekly C-P tablet, since it was uncertain whether they had acquired malaria because they failed to take the prescribed medication while under treatment
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* Brig. Gen. Frederic J. Hughes, Jr., Director, Professional Services Division: Disposition form to the Deputy Surgeon General, 23 Nov. 1965.
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(secondary gain), or whether there was indeed a drug-resistant strain involved. The treatment failure rate was 43 percent: 70 of 163 patients had relapses, most of them within 3 weeks, although several relapses occurred as late as 69 days after completion of treatment, attesting to the resistance of P. falciparum in this group. Three regimens were then evaluated, using pyrimethamine, quinine sulfate, and a combination of both. The results appear in table 48. The superiority of combined quinine sulfate-pyrimethamine therapy was again clearly demonstrated in a 12-day schedule with a low recrudescence rate (1.3 percent).
Reed, Feinstein, and Steiger (1968) analyzed the results of treatment in malaria patients at the U.S. Army Hospital, Camp Zama, Japan, between August and December 1965. Of 462 patients admitted with a diagnosis of falciparum malaria, 426 were selected for study because they satisfied the criteria for diagnosis and their records were adequate. The recrudescence rate with 3-day chloroquine was 89 percent a month after treatment and was not improved with repeated courses. Quinine alone effected a radical cure in 50 percent, but this was because of the inclusion of a group receiving the drug for periods up to 30 days. In another small group on pyrimethamine alone, the cure rate was 91 percent, but dose range was not indicated. The best regimen was quinine-pyrimethamine, with which a 95-percent cure was obtained; the total dosage range of pyrimethamine was usually 75 to 150 mg, reaching 400 mg in
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some patients, while quinine was given for 3 to 12 days and in several instances as long as 30 days.
Despite the apparent effectiveness of 14-day quinine and 3-day pyrimethamine therapy, investigation continued into available drugs which might increase the effectiveness of the therapeutic regimens and of C-P prophylaxis. In Sheehy and Reba`s original study (1967), dapsone (4,4`-diaminodiphenylsulfone) as a supplement to a chloroquine-quinine regimen had given promising results; only 1 of 105 patients had a recrudescence during the 30-day supplemental dapsone treatment. Interest began to focus on this compound.
The antimalarial properties of the sulfones had been recognized by the Italians in World War II (Tarabini-Castellani and Secreto 1945). Dapsone had been used in the treatment of leprosy since 1949; in a daily dose of 100 mg or less, it was considered relatively nontoxic. However, Lowe and Smith (1949) described a "mononucleosis syndrome" and a peripheral dermatitis caused by sulfones in patients with glandular fever, and McKenna and Chalmers (1958) established a relationship between agranulocytosis and dapsone administration.
Among lepers treated with the drug in certain areas of Africa, it was observed that the incidence of clinical malaria was lower than among the indigenous population. In the early 1960`s, investigators in India and Nigeria demonstrated that a single 200 to 250 mg dose of dapsone produced a clinical cure in semi-immune patients with falciparum malaria. Although the initial response was favorable in some patients, treatment failures were frequent. Dapsone was less effective in clearing parasitemia caused by vivax infections (Basu, Mondal, and Chakrabarti 1962). Subsequent volunteer studies conducted under the Army Malaria Research Program demonstrated that dapsone, 25-50 mg daily, decreased severity of infections with two strains of chloroquine-resistant P. falciparum from Southeast Asia (DeGowin et al. 1966; Eppes et al. 1967). When the 25-mg daily dose of dapsone was used with the weekly C-P tablet before the infection was introduced, and continued for 4 to 6 weeks afterwards, suppression of infection and a radical cure were attained. These results prompted field trials in American troops stationed in Vietnam. In November 1965, Maj. (later Col.) Robert J. T. Joy, MC, then chief of the U.S. Army Medical Research Team, Vietnam, a unit detached from Walter Reed Army Institute of Research, was encouraged to evaluate dapsone as
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chemoprophylaxis by Brig. Gen. (later Maj. Gen.) Robert E. Blount and Col. (later Brig. Gen.) William D. Tigertt, MC, during their visit to the country. A pilot study was conducted in January and February 1966 among personnel of the 1st Cavalry Division (AM); it suggested that dapsone was effective, without evidence of toxicity, and justified a more extensive evaluation. This was carried out-amid the difficulties of jungle combat conditions-in March and April 1966 with 12 companies of the 1st Brigade of the division, deployed to the west of Pleiku in the Central Highlands. The dose regimen for the study group was 25 mg dapsone daily plus the weekly C-P tablet. Six companies served as a control group. There was 50 percent less malaria in units taking dapsone than in units taking a placebo (Joy, McCarty, and Tigertt 1969).
The second part of the study was conducted in units of the 3d Brigade Task Force, consisting of the 3d Brigade, 25th Infantry Division, and elements of the 1st Cavalry Division (AM). The study took place during Operation PAUL REVERE I in the Ia Drang and Ya Lop River valleys along the Cambodian border where malaria was endemic. The entire task force, except for the two battalions from the 1st Cavalry Division, was placed on daily dapsone prophylaxis, 25 mg, in addition to the-weekly C-P tablet. Records of all patients admitted to the 85th Evacuation Hospital at Qui Nhon and the 8th Field Hospital in Nha Trang during the subsequent 2-month period were reviewed. The malaria incidence among troops taking dapsone was one-tenth of that observed in units not taking it. Other factors related to malaria discipline, such as use of repellants and wearing of long sleeves, were not controlled. This, and the fact that comparison was made between two divisions rather than within a single divisional force jeopardized definitive conclusions; nevertheless, the difference was striking (Joy, Gardner, and Tigertt 1969).
The next step was to acquire adequate stocks of dapsone and put to use the findings of these field trials. By the end of July 1966, The Surgeon General had instructed all commands of the changes in malaria treatment and in the chemoprophylaxis regimen (OTSG-MT). Dapsone, in addition to the weekly C-P prophylactic tablet, was to be used by troops at high risk of exposure to drug resistant P. falciparum as determined by the USARV (U.S. Army, Vietnam) preventive medicine officer. The recommended treatment of clinical cases consisted of quinine sulfate, 975 mg thrice daily for 2 days, then 650 mg thrice daily for 12 additional days; pyrimethamine, 25 mg every 8 hours for the first 3 days; and dapsone, 25 mg daily from day 7 to day 28. Personnel taking dapsone prophylaxis in Vietnam were required to remain on the drug for 28 days following departure from the country.
Another study was conducted in late 1965 and early 1966 by Sheehy et al. (1967) at the 85th Evacuation Hospital in Qui Nhon. This study involved 155 nonimmune American soldiers. The controls and the dapsone-treated patients received similar treatment regimens: both groups had the standard 3-day course of chloroquine (1.5 g), and both received quinine sulfate (650 mg thrice daily), the controls for 14 days and those on dapsone for 7 to 10 days. The experimental group received dapsone for 30 days. Only 3 percent (3 of 105) of the dapsone-treated patients had a recrudescence within 3 weeks, as opposed to
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41 percent (20 of 48) of the control group. Although 45 of the soldiers studied were black, only one hemolytic complication due to G6PD deficiency was observed Dapsone as a supplement to basic treatment schedules was clearly shown to be effective.
EXPERIENCES WITH QUININE-PYRIMETHAMINE-DAPSONE THERAPY, 1966-68
Implementation of the treatment regimen for chloroquine-resistant falciparum malaria which resulted from Joy`s field studies actually began in Vietnam in 1966. Dapsone, in addition to the daily C-P tablet, was authorized for use in major combat units of the I Field Force area, which extended from the Chu Lai region to the Laotian border and as far south as Da Lat. It was emphasized that any soldier on dapsone prophylaxis who acquired clinical malaria was to continue on the drug without interruption in daily dosage. This was important since it was learned very early that breakthroughs occurred when prophylaxis was interrupted for even a few days while soldiers were on rest and recuperation leave (Blohm 1966b).
Thus, the early recommended treatment for falciparum malaria was a 14-day quinine, 3-day pyrimethamine regimen in the following schedule (USARV Msg):
Quinine sulfate, 975 mg thrice daily, days 1 and 2, then 650 mg thrice daily, days 3 through 14.
Pyrimethamine, 25 mg thrice daily, days 1 through 3.
Personnel on daily dapsone were to continue daily dosage of 25 mg without interruption. Table 49 shows the reduction in major complications which occurred after standardization of therapy.
The weekly C-P tablet was discontinued during therapy for falciparum malaria and resumed immediately afterwards. The combination of primaquine and dapsone had the potential for causing marked hemolysis and methemoglobinemia in susceptible individuals. A convalescent period of 10 to 14 days was recommended and extended if a significant anemia persisted (hematocrit less than 36). With the opening of the 6th Convalescent Center, at Cam Ranh Bay, patients with malaria could complete treatment and convalescence and then engage in a graduated physical fitness program that would
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insure their return to duty in a combat-ready condition. Original peripheral blood smears accompanied the patient through the chain of evacuation, so that the diagnosis could be confirmed or, in recrudescences, errors could be uncovered or mixed infection diagnosed (Blohm 1966b).
The standardization of therapy permitted studies evaluating drug efficacy, toxicity, and detection of signs of drug resistance. Consequently, after only a few weeks, it became apparent that the increased dosage of quinine during the first 2 days of therapy was not well tolerated; nausea and vomiting occurred frequently. Furthermore, high doses actually contributed little to the prompt lysis of fever and further recovery. A three-times-daily dosage of 650 mg of quinine sulfate through the entire treatment course was adopted (Cooper 1966).
Blount (1969) reviewed the first year`s experience at the 85th Evacuation Hospital at Qui Nhon. The only modification in therapy after the reduced total quinine dosage was adopted was to further decrease the pyrimethamine dosage from 225 mg to 150 mg over the 3-day period. This reduction was prompted by the increased development of megaloblastic anemia in patients treated with the higher dosage and, in the later years of the war, was officially adopted in preference to the 225 mg total dose. Early studies had demonstrated that continued administration of 25 mg of pyrimethamine daily resulted in megaloblastic anemia, leukopenia, and maturation arrest of the bone marrow (Myatt, Hernandez, and Coatney 1953; Kaufman and Geisler 1960). At the 85th Evacuation Hospital, a sulfonamide was substituted in the occasional patient with megaloblastic anemia without documented difference in response. When parenteral quinine therapy was indicated, 650 mg of the hydrochloride was diluted in 1,000 cc 5-percent dextrose/water or isotonic saline and infused intravenously over an 8-hour period and repeated every 8 hours until oral medication was tolerated. The oral dose regimen was as follows:
Quinine sulfate, 650 mg every 8 hours, days 1 through 14.
Pyrimethamine, 25 mg every 12 hours, days 1 through 3.
Dapsone, 25 mg daily, when the patient was taking the drug as prophylaxis.
Table 50 gives the total number of admissions to the hospital from September 1966 until the end of August 1967; 35 percent of all medical admissions were for malaria, of which 75 percent were falciparum, 22 percent vivax,
TABLE 50.- Malaria admissions, 85th Evacuation Hospital, September 1966-August 1967
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and 3 percent mixed. Malariae malaria was diagnosed in 12 patients, one of whom had a mixed infection with Plasmodium vivax. P. vivax and Plasmodium malariae infections were treated in the conventional manner with no difficulty. Mixed falciparum-vivax infections were treated with chloroquine and primaquine in addition to the basic regimen for falciparum malaria. The recrudescence rate for falciparum malaria was less than 1 percent during the 4-week followup period. There were no deaths in this series. The complications of falciparum malaria that were observed are listed in table 51. Hemoglobinuria, an indication of the density of parasitemia and extent of hemolysis, was present in eight patients. Acute renal failure was not seen in this series. Twenty-four patients had neurological abnormalities indicative of cerebral malaria; an adrenal corticosteroid, either dexamethasone or hydrocortisone, was used with parenteral quinine in these patients, sometimes with dramatic response. The role of parenteral steroids in the reduction of cerebral edema was unclear; however, clinical use of them was widespread in Vietnam and anecdotal evidence was strong that they hastened the response to quinine. Anemia severe enough to require transfusion was another hematologic complication in 18 patients. Eleven had pancytopenia when admitted or at the start of multiple drug therapy, with recovery beginning during the first week of therapy in most. Methemoglobinemia was observed only once, and acute hemolysis secondary to GOD deficiency was an occasional finding.
Because of the concern that quinine might have been responsible for some of the more severe hematologic complications, it was desirable to learn whether the amount needed to effect a clinical cure could be reduced. There was also a need to reduce the number of days lost from duty, which at this time was estimated by the medical consultants * to be 30 to 35 days for falciparum malaria. Longer patient observation periods had been required during the latter half of 1966 to assess drug efficacy.
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Further contributions to standardization of therapy for falciparum malaria were made in January 1967, at the 6th Convalescent Center. Rogoway and Bailey (1967) conducted a study to determine whether the duration of quinine therapy could be reduced from 14 to 10 days, consequently reducing the total dosage, without risking an increased relapse rate. Two groups, comparable in age and race, were evaluated, totaling 141 patients (table 52). The same drugs were used in both groups; quinine 650 mg thrice daily for 10 or 14 days, pyrimethamine 25 mg thrice daily for 3 days, and dapsone 25 mg daily. Only the duration of quinine therapy was varied. All patients were followed up 21 days after completion of quinine treatment. There were no treatment failures in either group. Three patients on the 14-day regimen had complications: one developed a drug reaction with high fever, headache, maculopapular eruption, and arthralgias; a second had megaloblastic anemia; a third had vivax infection breakthrough. No complications were observed with the shorter regimen and length of hospital stay was shortened by 3 days. The USARV surgeon adopted this shorter regimen in July 1967 for use in all treatment facilities in Vietnam.
The early field trials with sulfonamides were restricted because of the limited availability of these drugs in field hospital pharmacies and even in larger military medical centers in the United States. They were never used alone because of their low activity against falciparum strains. Used in various combinations, they failed to influence the recrudescence rate. There was a certain rationale in using them in combination with antifolate drugs such as pyrimethamine, however. Sulfonamides were known to compete with para-aminobenzoic acid in folic acid synthesis, and pyrimethamine to interfere with the action of dihydrofolic acid reductase; thus there was a two-pronged attack on folic acid synthesis, which is essential to the formation of plasmodial nucleotides. It had been recognized for some time that the action of pyrimethamine could be potentiated by sulfonamides and even prevent the emergence of resistance (Hurley 1959).
Laing (1965) reported that a long-acting sulfonamide, sulforthodimethoxine (Fanasil), when administered to semi-immune Africans with falciparum malaria
TABLE 52.- A comparison of 10- and 14-day quinine in multidrug therapy for acute falciparum malaria
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as a single dose in a range of 250 to 1,000 mg, produced a rapid clinical and radical cure. The compound is an isomer of sulfadimethoxine (Madribon) with a biologic half-life of 100 to 200 hours. This is 25 times the half-life of sulfisoxazole and is attributable to its slow excretion in the urine (Bartelloni, Sheehy, and Tigertt 1967). Theoretically, a 1-g dose of Fanasil is equivalent to a 1-g daily dose of another long-acting compound, sulfamethoxypyridazine (Kynex). Peak blood levels of Fanasil are reached 4 hours after ingestion and the compound is excreted in the urine slowly.
Bartelloni, Sheehy, and Tigertt (1967) conducted preliminary trials with these compounds at the 3d Field Hospital in Saigon in 1966. The posttreatment observation period ranged from 28 to 63 days. Ten patients with recrudescent falciparum malaria had a clinical cure with a single 1-g dose of Fanasil plus 50 mg pyrimethamine. Five patients with an initial infection also had a rapid clinical cure with this regimen. Triple-drug therapy in 55 patients with initial infection, using the same single dose combination of Fanasil and pyrimethamine, plus quinine 650 mg every 8 hours for 14 days, was also highly effective with only one clinical relapse 3 days after treatment was completed.
Several other studies were conducted at the 3d Field Hospital and the 93d Evacuation Hospital during this period. Eighty-four patients were treated with quinine for 14 days, pyrimethamine for 3 days, and Fanasi1500 mg on day 1. Only one recrudescence was observed. Fifty-nine patients were treated with quinine for 14 days, pyrimethamine for 3 days, and sulfisoxazole (Gantrisin) 50 mg thrice daily for 5 days, with no recrudescences. However, the posttreatment observation period did not exceed 16 days (Blohm 1966a). A few trials with sulfadiazine were carried out in late 1965 in combinations with chloroquine or quinine.
Berman (1969) reported his experiences with triple-drug therapy in a study of 99 marines. Chloroquine was given in the standard dosage of 1.5 g base over 3 days. Pyrimethamine was administered in a 50-mg initial dose, followed by 25 mg every 8 hours for 10 doses, for a total dosage of 300 mg. Sulfisoxazole was also given concurrently, 4 g daily in divided doses for 6 days, for a total of 24 g. There were no treatment failures among the 76 patients whose cases could be followed up.
Because of the recognized problem of drug resistance and the relatively slow activity of sulfonamides, large-scale clinical field trials with these drugs were discouraged; it was preferable to await the development and testing of new compounds in this class under controlled conditions. A USARV regulation (USARV Reg) on the treatment of malaria permitted the use of sulfonamides for treatment failures but only in combination with quinine and pyrimethamine.
Sheehy and Reba (1967) reviewed the early experience with sulfadiazine in multiple drug therapy and devised a 14-day quinine, 3-day pyrimethamine regimen combined with sulfadiazine 0.5 g every 6 hours for 5 days concurrently. Radical cure was effected in 57 of 60 nonimmune soldiers. All 40 patients treated with another regimen, chroroquine-quine-quinine- pyrimethamine-sulfadiazine, also had radical cures (see table 47). Chin and coworkers (1966) evaluated the effectiveness of sulfonamides used alone or in combination with pyrimethamine. Volunteers were infected with drug-resistant strains and sulfadiazine, Fanasil,
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and sulfamethoxypyridazine were employed. Again, these drugs were slow in reducing parasitemia and in terminating the acute attack, even when used with pyrimethamine. The combination of pyrimethamine and sulfadiazine was inferior to the other two combinations. The most effective was 50 mg pyrimethamine and 1 g Fanasil given as a single dose. Powell, DeGowin, and McNamara (1967) evaluated the efficacy of sulfadiazine and pyrimethamine in volunteers infected with the chloroquine-resistant Malayan Camp strain, Thailand (JHK) strain, and Vietnam (CV) strain of P.falciparum. They confirmed previous observations that combinations of a sulfonamide and pyrimethamine are ineffective in potentiating the blood gametocidal effect. They also found that sulfadiazine alone does not satisfactorily treat acute drug-resistant strains of falciparum malaria; however, under certain conditions, when combined with pyrimethamine, its therapeutic efficacy is enhanced and it may be useful in treating individuals infected with chloroquine-resistant strains of P. falciparum.
VIVAX MALARIA
Although vivax malaria was prevalent throughout South Vietnam, and there were indications that the attack rate among the Vietcong was high, few cases were reported in U.S. troops during the early period, indicating good malaria discipline, especially in terms of chemoprophylaxis. There were no reported cases of vivax malaria in the last half of 1965 (AMEDS/AMEDD- AR65, pp. 20-21). P. vivax and P. malariae infections were less likely to be acquired during the dry season or cool months of the year. This was the experience with vivax infections acquired in Korea; recrudescences were usually observed in the late spring and summer when the mean ambient temperature exceeded 70?F (Neel 1973, p.13).
Later in the war some concern was expressed that drug-resistant strains of P. vivax were emerging, particularly when the attack rate rose in 1967. The clearly increasing attack rate among personnel returning to the continental United States, however, could be traced to unsupervised, inadequate terminal chemoprophylaxis.* Approximately 1 in every 100 Vietnam returnees was infected with malaria in 1967, a fact that prompted The Surgeon General (Heaton 1967) to inform all medical commanders of the situation.
Many explanations were offered for the failure of troops to take the C-P tablet regularly. First, it required discipline to take the tablet once a week voluntarily, particularly under conditions of jungle fighting, although some units employed a malaria roster and a system to insure that each soldier swallowed a tablet as he approached the mess line each Monday. Second, the pill was believed to have various side effects. The incidence of gastrointestinal symptoms was reportedly high and diarrhea 24 hours after ingestion was not uncommon, an undesirable situation in a combat operation. Some who took the pill complained
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1 On 4 Apr. 1966, a circular (DA Cir 40-24) was published, requiring all cases of malaria diagnosed at a U.S. Army medical facility to be reported to local or state health authorities, to The Surgeon General, and to the National Communicable Disease Center in Atlanta. Imported malaria was now a matter for strict surveillance.
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of insomnia, but this symptom was especially difficult to evaluate (Conte 1968).
"Folklore" aside, some serious side effects were reported. In 1968, the 3d Surgical Hospital reported a death from anaphylaxis after ingestion of a C-P tablet (SH-3), and unconfirmed reports of anaphylaxis and death following ingestion of a C-P tablet reached the medical consultant in 1969.* In 1970, the medical consultant documented a case of bronchospasm on challenge with a C-P tablet (Edgett 1970). The offending agent was probably the chloroquine component. Fortunately the incidence of such reactions remained inconsequential. Physicians were continually aware of significant hemolytic reactions in both whites and blacks. A number of patients were evacuated each month because of self limited but severe hemolytic episodes (AMEDS/AMEDD-AR69, p. 14). This was not unexpected on the basis of the conclusions of George, Sears, and Conrad (1966). In studying three whites and one black with G6PD deficiency, they found that assay of G6PD or measurement of pentose shunt activity did not directly provide a basis for the prediction of primaquine sensitivity. Chart 17 demonstrates the response of a primaquine-sensitive patient to a single C-P tablet.
In addition to possible allergic reactions to chloroquine and hemolysis related to primaquine, cyanosis during malaria chemoprophylaxis was a cause of evacuation of U.S. soldiers. Study of the effects of both dapsone and primaquine demonstrated that significant methemoglobinemia could occur in NAD (nicotinamide-adenine dinucleotide) methemoglobin reductase-deficient subjects. Because of the cyanosis produced by these drugs, clinical recognition of a usually undetected enzymatic defect of the erythrocyte became possible. At levels above 20 percent methemoglobinemia, Cohen et al. (1968) noted headache, dizziness, anorexia, nausea, and vomiting. Whether a lesser degree of methemoglobinemia produced impaired function in the combat soldier was unclear. Aviators were not affected because they did not generally participate in malaria prophylaxis.
Between 1 September and 1 December 1966, 1,309 cases of malaria were treated at the 85th Evacuation Hospital in Qui Nhon, of which 13 percent (165) were vivax infections. The vivax response to chloroquine was always prompt, giving added support to the belief that poor malaria discipline was the decisive factor in the development of clinical vivax malaria.** At the 6th Convalescent Center, Carbon (1967) reviewed the experience with vivax malaria from 1 June 1966 to 30 April 1967, because it had been observed that the recrudescence rate had risen significantly when the treatment schedule was changed in December 1966, resuming the weekly C-P tablet in lieu of 14-day primaquine therapy. Whereas, at the end of December 1966, 6 percent of the total malaria cases at the 6th Convalescent Center were caused by P. vivax, by the end of April 1967 this figure had increased to 17 percent. The recrudescence rate had also changed
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*Lt. Col. Andre J. Ognibene, MC, USARV Medical Consultant, 1969.
** Maj. Robert E. Blount, Jr., MC. Note to Brig. Gen. Robert E. Blount, Commander, U.S. Army Fitzsimons General Hospital, forwarded to Col. Marshall E. McCabe, MC, 16 Dec.1966.
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CHART 17.- Response of primaquine-sensitive patient to a single C-P tablet
from slightly more than 12 percent to 18 percent, and a majority of the patients who experienced a relapse did so in the hospital, where they presumably had not
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been taking the C-P tablet.* As a result of this and other experiences, the USARV surgeon changed the policy for the treatment of vivax malaria to include the concurrent administration of 15 mg primaquine base daily for 14 days, in lieu of the weekly C-P tablet, in treatment schedules and on departure from Vietnam. No change was prescribed for field chemoprophylaxis (USARV-CG).
One other aspect of weekly C-P chemoprophylaxis deserves mention. In and around base camps, it was not uncommon for personnel to avoid the side effects attributable to primaquine by substituting a chloroquine tablet (300 mg base). To what extent this was practiced in the field is not known, although the consensus was that most personnel took the C-P tablet, if only erratically (Conte 1968). Powell (1966) had shown that primaquine, like pamaquine, exhibited sporonticidal and gametocidal activity against drug-resistant falciparum strains. In the standard 45-mg primaquine dose, it not only eliminated the gametocytes that would ordinarily circulate in the peripheral blood but also inhibited parasite development in the mosquito vector (Rieckmann et al. 1968). Thus, the use of chloroquine alone was unwise since primaquine prevented troops from becoming a source of falciparum infection in areas where they were based.
Throughout 1968, it was evident that the inclusion of 14 days of primaquine in the treatment regimen for vivax infections had virtually eliminated the problem of early relapse observed in late 1966 and early 1967 (Conte). However, this was of little comfort in the face of the persisting primary incidence rate, which reached 31.5 per 1,000 by October of 1968 (USARV-CHR Oct. 68).
A consequence of this problem was the increasing number of malaria cases reported in the United States each year from 1965 through 1971. Canfield (1972), using Center for Disease Control malaria surveillance reports, determined that during this 6-year period more than 14,000 cases of vivax malaria were reported in the United States, accounting for over 80 percent of the country`s total malaria cases. The data provided by Barrett et al. (1969) in their survey of 671 Vietnam returnees indicated that this was largely the result of failure to complete the prescribed terminal chemoprophylaxis regimen, as was the case in 70 percent of their group. This was a serious indictment of the method of administration, for the C-P tablet, though highly effective in itself, had to be taken faithfully for 8 weeks by individuals who were apparently in good health.
TREATMENT OF MALARIA, 1968-7 2
In January 1968, an analysis of 1,000 consecutive cases of falciparum malaria admitted to the 6th Convalescent Center during the months of November and early December 1967 - when the attack rate was at its peak - indicated that the treatment failure rate approximated 1 to 2 percent with the 10-day triple-drug regimen, quinine-pyrimethamine-dapsone. Most patients at the center were returned to duty within 5 days after completion of therapy. The average time lost from duty for falciparum malaria was now 24 days; for vivax
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* Figures modified by Brig. Gen. Andre J. Ognibene.
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malaria, it was 12 days (Conte 1967). Some units, such as the 173d Airborne Brigade, were experiencing very high attacks rates; approximately half of the infections were vivax, indicating a breakdown in malaria discipline. The evidence notwithstanding, there was still some lingering concern that strains of P. vivax present in Vietnam were not responsive to the weekly C-P tablet as a suppressant.
In 1969, Hiser et al. (1971) conducted a study of the 71st Evacuation Hospital, Pleiku, where a group of 30 patients with acute vivax malaria was evaluated. A second group of 12 vivax patients was studied at Walter Reed General Hospital, Washington, D.C. The group in Vietnam was treated with a single C-P tablet weekly for 2 weeks and returned to duty at the end of the second week. Urine chloroquine determinations were made before and 1 week after the first C-P tablet. No patients had evidence of urine chloroquine before treatment; two-thirds had a positive urine test a week after receiving a single C-P tablet. Plasma chloroquine levels were not measured. The Walter Reed group was treated with a single C-P tablet, observed for 3 weeks, and then given the standard treatment to effect a radical cure (3 days of chloroquine plus 14 days of primaquine). All patients in both groups responded to treatment promptly with no relapses. This fact, and the absence of residual chloroquine from the urine of all patients in the Vietnam group on admission, gave added support to what many had suspected all along: the most important factor in the high incidence of vivax infections in selected U.S. troops in Vietnam was failure to take the chemoprophylactic tablet regularly.
The remarkable success of the 10-day quinine-pyrimethamine regimen against falciparum malaria prompted some to wonder whether treatment could be shortened again, thereby reducing drug-related morbidity and days lost from duty even further. Reback, Theus, and Freebern (1968) conducted a study at the 6th Convalescent Center at the end of 1967 to evaluate a 7-day course of therapy with the daily dosage of quinine and pyrimethamine remaining the same; the total amount of quinine administered was thus reduced from 4.6 to 3.2 g. The treatment failure rate in 135 cases was about 6 percent, indicating the inferiority of this shortened regimen.
Meanwhile, the search for more effective sulfonamides continued, because induced resistance was a real danger and drug combinations with pyrimethamine had certain limitations. One promising compound was sulfamethoxy pyrazine (2-sulfanilamide -3-methoxypyrazine), or sulfalene, which also acts as an antifolate through its competitive inhibition of para-aminobenzoic acid. Its half-life is approximately 63 hours (Martin and Arnold 1968a). Early clinical trials of sulfonamides against acute falciparum infections in Africans were encouraging, although some workers reported disappointing results. However, success with Fanasil and pyrimethamine against chloroquine-resistant falciparum malaria had been reported by Bartelloni, Sheehy, and Tigertt (1967) at the 3d Field Hospital. Martin and Arnold (1968a) evaluated the sulfalene compound in volunteers, using the drug-sensitive East African Uganda I strain and the drug resistant Malayan Camp strain. Curiously, the drug, given as a single dose, was more effective against the drug-resistant Camp strain. Furthermore, with
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relative resistance to pyrimethamine, the Uganda I strain`s sensitivity to sulfalene was enhanced. As the authors point out, this suggests that there are qualitative differences in the actions of sulfonamide drugs.
Martin and Arnold (1968b) also evaluated the efficacy of sulfalene in combination with trimethoprim [2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine], a dihydrofolate reductase inhibitor which was developed out of a survey of pyrimidine antibacterial compounds and was demonstrated to have less toxicity than pyrimethamine, with a relatively short half-life of 16 hours. Volunteers in this study were infected with the same strains, Uganda I and Camp. A single dose of 0.75 g sulfalene plus 0.5 g trimethoprim was used to treat infections with Camp strain, while the Uganda I strain was treated with smaller single doses of both drugs. All eight patients with the nonresistant Uganda I strain of P. falciparum were cured more rapidly than with quinine; 10 of 11 patients with the multiresistant Camp strain were cured.
Late in 1969, Canfield et al. (1971) conducted field trials with this drug combination among soldiers at the 71st Evacuation Hospital with naturally acquired falciparum malaria. This group was compared with a group of patients at Walter Reed General Hospital who had documented recrudescences from previous therapy. The patients in Vietnam received one oral dose of trimethoprim 1.5 g and sulfalene 1.0 g and were followed up for at least 35 days. The patients at Walter Reed were divided into two subgroups: one received trimethoprim 250 mg twice a day and sulfalene 250 mg four times a day on days 1, 3 and 5, while the other received trimethoprim 500 mg three times a day and sulfalene 250 mg four times a day for 3 days. All patients were followed up for 5 to 10 weeks. The results are shown in table 53. In group 1, only one patient failed to respond to treatment. In group 2, there were four treatment failures after a satisfactory initial response. The overall cure rate of 72 percent compared unfavorably with
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that obtained with the 10-day quinine-pyrimethamine regimen, demonstrating the necessity of carefully performed field trials of new compounds whose initial success in a controlled environment often results in premature or optimistic claims.
During the early part of 1969, uneasiness developed about the toxicity of dapsone, particularly since sentiment was growing to institute dapsone prophylaxis Army-wide in Vietnam. Previously, a large number of soldiers had been taking the drug without untoward effect although it was known to cause hemolysis and methemoglobinemia. By the end of the year, Ognibene (1970) reported 16 patients who had developed agranulocytosis while on dapsone prophylaxis and were admitted to Army hospitals in Vietnam; 50 percent of them died from overwhelming sepsis. None of these patients had been on dapsone for less than 4 weeks or more than 12 weeks; thus, the 28-day treatment schedule in combination with quinine and pyrimethamine appeared not to be in jeopardy. Agranulocytosis was not recorded in any U.S. personnel who were on C-P prophylaxis alone during this period. There was some suspicion that storage of dapsone for extended periods under high temperatures had resulted in deterioration, but subsequent studies carried out at WRAIR (Walter Reed Army Institute of Research) failed to substantiate it.
Consequently, the policy concerning dapsone prophylaxis was modified (USARV Reg). Dapsone was not required as prophylaxis against falciparum malaria except when combat operations occurred in known or suspected hyperendemic falciparum malaria areas. In such cases, commanders of divisions, separate brigades, and similar elements were granted authority, upon the advice of the command surgeon, to begin or continue dapsone chemoprophylaxis. Dapsone was considered necessary when exposure of U.S. military personnel to malaria might result in unacceptable manpower losses (more than 20 cases per 1,000 per year).
Because of its ability to induce methemoglobinemia, dapsone also produced cyanosis; this effect was potentiated by the concurrent use of primaquine. Studies demonstrated that about one in three troops receiving dapsone and the C-P tablet had a methemoglobin level in excess of 2.5 percent (MRP-Rev, p. 3). The Australian forces abandoned the use of dapsone in 1970. Thus, the treatment regimen for falciparum malaria became a short course of a sulfonamide, such as sulfisoxazole, in combination with other drugs, rather than dapsone for 28 days. Experimental data suggested that a diformyl derivative, DFD (4,4`-diformaminodiphenylsulfone) was more effective than dapsone. The antimalarial activity of DFD in rodent and P. berghei malaria had been demonstrated before World War II (Aviado 1967). Since it could be administered once a week, the serious complications experienced with dapsone could be reduced, although methemoglobinemia remained a serious drawback. However, U.S. troops were withdrawing and field trials were not carried out in Vietnam (Clyde et al. 1970).
Reports from the Naval Medical Research Unit No. 2 in Da Nang (Tong et al. 1970) suggested that the anemia, leukopenia, and thrombocytopenia in patients with malaria which became more severe during treatment with drugs
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such as sulfonamides and pyrimethamine could be reversed by administration of 5 mg of folic acid daily. In 75 patients studied, no interference with antimalarial therapy was noted. Hematocrit, white count, and platelet count showed striking improvement in the folate-treated groups (charts 18, 19, and 20).
By 1970, there were indications that the "quinine regimen" which had served since 1966 was losing efficacy. Hall (1970; 1971) analyzed the experience with the standard 10-day quinine-pyrimethamine regimen at the 6th Convalescent Center in 792 patients admitted from 20 November 1969 to 23 February 1970. The recrudescence rate was 9.6 percent. The trend since 1965 is depicted in table 54.
Several reasons were offered in explanation of this trend, including differences in drug resistance with respect to geographic areas, poor or irregular absorption of quinine tablets, poor tolerance to ingestion of the drug, and deliberate avoidance (Hall 1970; 1971). It was recognized that drug-resistant malaria was most prevalent in troops engaged near the Cambodian border northwest of Saigon. Geographical differences are reflected in relapse rates with respect to referring hospital, as shown in table 55. Hospitals supporting III CTZ (Corps Tactical Zone) operations all had relapse rates over 10%.
Jolson et al. (1970) conducted a study in healthy volunteers comparing quinine blood levels produced by tablets and by capsules. Capsules produced much higher blood levels after the first dose, although the sustained blood levels over the next 10 days were only slightly higher.
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335
Hall (1970) conducted clinical trials comparing oral and intravenous quinine regimens over a 10-day period. Dapsone 25 mg daily for 28 days was initiated when the sulfonamide therapy was completed. Intravenous quinine was given as the hydrochloride salt 1,300 mg per 1,000 ml isotonic saline over an 8-hour period for 10 days (total 19.5 g). Preliminary studies had suggested that quinine given by continuous intravenous infusion effected a radical cure in a greater number of patients. Final results, which demonstrated the superiority of parenteral quinine therapy, are indicated in table 56. Retreatment of failures with the standard oral program resulted in cure in only 33 percent of the patients as compared with 89 percent when the quinine was given intravenously. The only side effects of parenteral therapy were transient tinnitus and deafness in a few patients, while
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TABLE 56.-Therapy of patients who had one relapse after treatment of falciparum malaria
anorexia, nausea, and vomiting occurred more frequently in patients taking oral medication. Any patient who failed to respond to intravenous therapy was considered to have a severe drug-resistant infection. The conclusions of this study were not to be construed as a recommendation for routine intravenous therapy but to emphasize that drug resistance can be relative and variable.
The routine use of a specific drug over a period of time allows evolution of resistant mutations of the parasite. In this study, a small number of patients with repeated recrudescences in spite of a rigorous therapeutic program had to be evacuated to Walter Reed Army Medical Center and treated with investigational drugs from the Army Malaria Research Program (Hall 1971). The strains isolated from these patients were made available for study of new compounds in the clinical centers.
In 1970 and 1971, two other classes of drugs received limited clinical trials because of the intensified effort in the Army Malaria Research Program. One group was the arylaminoalcohols, of which the phenanthrene methanols received the most attention. The prototype was designated WR 33063 (6-bromoa-[diheptylaminomethyl]-9-phenanthrenemethanol). In controlled studies with P. falciparum-infected nonimmune volunteers, Arnold et al. (1973) reported excellent results with a dosage of 0.4 g four times a day for 6 days. A radical cure was obtained in 18 of 22 volunteers infected with the Vietnam (Smith) strain, all 6 with the Vietnam (Marks) strain, 2 of 3 with the Vietnam (Brai) strain, all 5 with the Malayan Camp strain, and all 6 with the Uganda I strain.
Canfield et al. (1973) conducted a field study to test the efficacy of these drugs in the treatment of primary falciparum infections acquired in Vietnam, as well as a study of patient response with multidrug-resistant malaria. A radical cure was effected with the phenanthrene methanol WR 33063 in 23 of 25 patients admitted to the 93d or 24th Evacuation Hospitals in Vietnam with an acute attack of falciparum malaria.
Another compound of interest was quinoline methanol WR 30090 (6,8-dichloro- 2-[3`,4`-dichlorophenyl]-a-[di-n-butylaminoethyl}4-quinolinemethanol hydrochloride). Volunteer studies using a dosage of 230 mg every 8 hours for 6 days demonstrated its efficacy against several P. falciparum strains. Cure was achieved in all 6 of the Uganda I strain, all 6 of the Malaya (Taylor) strain, all 6 cases with the Malayan Camp strain, all 5 with the Vietnam (Marks) strain, 2 of 3 with the Vietnam (Crocker) strain, and 17 of 20 with the Vietnam (Smith) strain
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CHART 21.-Incidence rate per month of falciparum and vivax malaria. USARV, 1965-71 1
CHART 22.-Number of cases per month of falciparum and vivax malaria, USARV, 1965-711
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(Martin et al. 1973). In the study of Canfield et al., quinoline methanol WR 30090 cured 23 of 26 patients with falciparum malaria in Vietnam as well as 8 patients with multiple recrudescences admitted to hospitals in the United States. Adverse reactions to the drugs were not reported.
The final tabulations of incidence rate and total cases of malaria in Vietnam are reflected in charts 21 and 22. It is probable that a final chapter on malaria chemotherapy will not be written; rather, a continuing chronicle of effort, discovery, and drug-resistant mutation will occur. The presence of drug-resistant P. falciparum strains in many areas of the world will pose a formidable threat and challenge in all future malaria eradication programs. The experiences with malaria in Vietnam emphasize that there is no room for complacency in the chemotherapy of this disease. The discovery of and encouraging results with several classes of new compounds such as the aminoalcohols, and more recently the quinazolines, attest to the value of a continuous Army Malaria Research Program. Only through the acquisition of new knowledge concerning the pharmacologic and biologic aspects of drug resistance in the malarial parasite can we hope for more rational and effective treatments against this important scourge of mankind and formidable foe of all field armies.
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