THE USE OF LONG ACTING SULFONAMIDES. ALONE OR WITH , IN MALARIA (WITH SPECIAL REFERENCE TO SULFORMETOXINE)

J. Herrero **

The antimalarial activity of the sul- It is somewhat astonishing that no fonamides was described very soon major work was carried out during after the discovery of these drugs. the years from 1955 to 1963, i.e. du­ As early as 1940, a number of pa- ring the períod in which, thanks to pers, such as those by Diaz de León the discovery of the so-called long- (31-33), Hill and Goodwin (56), Van acting sulfonamides , a better know- der Wielen (129), Coggeshall (18- ledge of the pharmacokinetics of the­ 20, 23), Niven (83), Chopra et al. se drugs was obtained. It is now evi- (10-13), Menk and Mohr (81), Fa- dent that many of the early contra- rinaud et al. (37-38), Sorley and dictory reports regarding the antima­ Currie (118), Sinton et al. (117), larial effect of sulfonamides, made etc., had reported on a somewhat va- during the initial years of the sul- riable success obtained with sulfona- fonamide era, were due to the scanty mides in experimental and human Information on the pharmacokinetics malaria. For a further 10 years, i.e. of these substances in man and in until 1950, there still existed some in- laboratory animais, a gap which led terest in this chemical group, as re- or misled, among other things, to- flected in some im portant clinicai wards empirical and therefore not trials, for instance those by Fairley et quite reliable dosage. al. (36) and by Coatney et al. (16, 17). At present, the reported resistance However, with the advent of more re- of certain Plasmodia strains to some liable synthetic antimalarials, chemo- major antimalarials such as pyrime- therapeutic work on sulfonamides thamine, and perhaps with prac^ical aims was almost dropp- even , and, on the other hand, ed and rather remained limited to the availability of some sulfones and basic questions of more theoretical in- sulfonamides with a very sustained terest like mechanism of action, po- action, have made it advisable to re­ tentiation of the effect of other anti­ examine the possible value of these malarials of the folic-acid-antagonist substances as an auxiliary tool for group on experimental malaria, cross the management of malaria. It is resistance, etc. This work is linked to renowned names such as Greenberg, most unfortunate that this logical in- Rollo, Goodwin, Bishop, Eyles and Co- terest is hampered by the reports on leman, Hitchings, etc. cases of Stevens-Johnson and Lyell Excellent cumulative reviews on sul­ syndrome, observed during the use of fonamides and malaria have been some of these substances. made by Curd (27) in 1943, Findlay The purpose of this short review is (42) in 1951, and Hill (58) in 1963. to summarize: a) the available infor-

(•) Paper presented at the Kound Table Coníerenee on Malaria (Belo Horizonte, August 2, lütiti) which followed the III International Pharmacological Congress in *São Paulo (July 24-30, 19ti'6) (**) Clinicai Rp.seareh Department, F. Hoffmann T.n Roche & Co.. Basle, Switzerland 10-*: Rev. Soc. Bras. Med. Trop. Vol. I — N? 3

mation on the effect of the sulfona- zathine rendered the gametocytes of mides on the different species and cy- P. falciparum incapable of developing cle stages of Plasmodia, b) their me- in the mosquito (Table IV). Howe- chanism of action and its implica- ver, Laing in his recent studies did tions, i. e.: potentiation and resistan- not find such an effect with Fanasil ce, and c) the trials so far carried out (70) . Further research on this sub- with the longest acting ject is therefore needed. There is no sulformetoxine, Ro 4-4393 *. information which would allow the As it can be seen from Tables I to assumption that sulfonamides possess IV, the effect of the sulfonamides has any activity as secondary tissue schi- been tested on the blood schizonts in zonticides in human malaria. Accor- most of the laboratory animal Plas­ ding to Bishop, exo-erythrocytic pa­ modia. They are considerably active rasites are “relatively insensitive” to against the blood schizonts of P. and (7). berghei, P. gallinaceum, P. knowlesi Mode of action of sulfonamides in and P. falcipamm and less or not ac­ malaria: It is paradoxical th at the tive in the rest. The results obtained mechanism of action of sulfonamffles, in cases of spontaneous or induced although not in ali its details, is bet- falciparum malaria have been almost ter known than that of most major unanimously positive although the antimalarials. Since the initial work onset of action of the sulfonamides by Maier and Riley (76), who proved is slower than th at of the major anti- in 1942 that the antimalarial effect of malarials. This has precluded their the sulfonamides is antagonized by p- use in the treatment of acute mala­ aminobenzoic acid, a number of stu­ ria. The results reported on malaria dies have been carried out, mainly by due to P. vivax are less uniform. So­ Greenberg, Goodwin, Rollo, Bishop, me authors find them to be effective Hitchings, Thurston, etc. (6, 47, 49, here (although always less so than in 50, 59, 60, 101, 102, 127). Sulfonami­ P. falciparum), whereas others (35, des, and pyrimethamine 36, 51, 81, 93, 106) find practically no constitute the group of the so-called therapeutic activity. This may have folic-acid-antagonist antimalarials, i. been due to differences in the dosage e. “those antimalarials whose ac­ or to the fact that the effects of dif­ tion has been considered to be concer- ferent sulfonamides vary considera­ ned with interference with the syn- bly (42). Very few investigations thesis of purines and pyrimidines via have been carried out with sulfona­ the PAB ■> folie acid * folinic acid mides in cases of malariae and ovale system” (102). According to Rollo m alaria. (Fig. 1), sulfonamides probably act Sulfonamides have a definite cau­ on reaction A by simple metabolite sai prophylactic effect against certain competition, whereas biguanides and Plasmodia such as P. knowlesi and pyrimethamine act in a more compli- P. gallinaceum (Table II). Regar- cated manner on reaction B. These ding human malaria, the reports are analogies and differences between the rather scanty, but it seems that sul­ mechanism of action of sulfonamides fonamides, at the doses tested, do not on the one hand and of the biguani­ act as causai prophylactics (16, 17). des and pyrimethamine on the other The sulfonamides do not exert any entail a complex framework of possi- effect on the gametocytes of the hu­ ble reciprocai effects when two of the­ man types of malaria (Table III). In se drugs are given together (poten­ fact, they can even increase their tiation) or in succession (cross resis- number in the blood (41). tan ce). Fairley et al. in 1945 and Findlay The possibility of cross resistance et al. in 1946 reported that sulfame- has been dealt with in several recent

(*) Trade name: Fanasil Boche (also mentioned íti the literaturc as snlforthomidine and aulforthodi- nietiioxine) . Table I Blood schizonticidal activity

Sulfonamides have been found active as blood schizonticides in:

Parasite References

P. berehei 29,57-58,82,94,98-100,124-12 5 P. gallinaceum 28,58,78,94,119,132 P. lophurae (less sensitive than 21,28,78,79 P. gallinaceum) P. fallax (less sensitive than 103 P. gallinaceum) P. circumflexum (less sensitive than P. gallinaceum) 77 P. knowlesi 10-11,18-23,92,95 P. cynoraolgi (less sensitive 21-23,53,116 than P. knowlesi P. inui (less sensitive than 20,21,23 P. knowlesi) P. falciparum 2,12-13,16,23,33,36-38,41,56, 66-69,71,73,75,81,83,89,106, 110,117,132 P. vivax (less sensitive than 12-13,17,23,37-38,56,61,73, P. falciparum) 118,132 P. malariae (less sensitive 12-13,23,26,37,45,110,129,132 than P. falciparum)

Sulfoaamides have been found inactive as blood schizonticides in:

Parasite References

P. lophurae 18 P. relictum 27,29,57,77 P. cathemerium 18,28,77,132 P. nucleophilum 77 P. vivax 35-36,51,81,93,106

BEST CLASSICAL BLOOD SCHIZONTICIDAL DRUGS: 4-AMINOQUINOLI.NES , QUININE, PYRIMETHAMINE, PROGUANIL OF THE ABOVE UNPRACTICAL FOR SUPPRESSION: MEPACRINE, QUININE UNPRACTICA1 FOR TREATMENT: PYRIMETHAMINE, PROGUANIL 106 Rev. So c. Bros. Med. Trop. Vol. I — N’ 3

Table II

Causai prophylaxls

Sulfonamides have been found active as causai prophylactics in:

Parasite References

P. knowlesi 42 P. cynomolgi (less sensitive than 53 P. knowlesi) P. gallinaceum 15,24,28-29,41-43,112,130 P. cathemerium* (canary) (less sensi­ 132 tive than P. gallinaceum) p. lophurae (turkey) (less sensitive 132 than P. gallinaceum) p. falciparum 117

Sulfonamides have been found inactive as causai prophylactics in:

Parasite References

P. falciparum 16,36,132 P. vivax 16,36 P. relictum 77 P. nucleophilum 77 P. cathemerium* (canary) 18,28,132 P. lophurae (chicks and ducklings) 18,28

* Some sulfonamides active; some others inactive

BEST CLASSICAL CAUSAL PROPHYLACTIC DRUGS: PROGUANIL AND PYRIMETHA- MINE (P. FALCIPARUM > P. VIVAX) ACTIVE BUT NOT PRACTICAL: 8-AMIN0QUIN0LINES Maio - Junho, 1967 Re v. Soc. Bras. Med. Trop. 10?

Table III

Gametocytocidal activity

Sulfonamides have been found inactive as gametocytocides in:

Parasite References

P. falciparum 14,33,36,42,70,111 P. vivax 42 P. malariae 42

BEST CLASSICAL GAMETOCYTOCIDAL DRUGS: 8-AMIN0QUIN0LINES

ACTIVE ONLY IN P. VIVAX AND P. MALARIAE: 4-AMINOQUINOLINES, MEPACRINE, QUININE

reviews (7, 58, 107-109) . Fig. 2 to 9 1) Sulfonamide-resistant strains of are a poor attempt to represent gra- some species of Plasmodia (e.g. phically the main observation of P. gallinaceum) are usually also cross or coincidental resistance in ex­ resistant to proguanil and pyri- perimental malaria due to Plasmodia methamine (7, 101). berghei, gallinaceum, cynomolgi and 2) Strains resistant to pyrimetha- knowlesi that have been reported. mine and proguanil or its triazine These figures make no claim to being derivative are generally not or complete or perfect since I may have . only partially resistant to sulfo­ missed some valuable reports. On the namides (85, 98, 101, 113, 115, other hand, there are some minor discrepancies in the literature, un- 122, 126). doubtedly due to differences in the 3) DDS-resistant strains are usually techniques used for creating resistan­ resistant to sulfonamides (8, 87- ce and to the inevitable differences 88, 90, 122). among the strains. 4) Usually there is no cross resistan­ Nevertheless, with regard to any ce between sulfonamides or sul- possible clinicai application of sulfo­ fones and antimalarials not be- namides (alone or combíned with longing to the group of the folic- pyrimethamine) the most important acid-antagonists. Frequently the­ facts about experimental cross resis­ re is even some hypersensitivity tance are: (55, 63, 84-88, 91, 120, 122) . 108 Rev. Soc. Bros. Med. Trop. Vol. I — N? 3

Table IV

Sporontocidal activity

Sulfonamides have been found active as sporontocidal drugs in:

Parasite References

P. falciparum 36,42

Sulfonamides have been found inactive as sporontocidal drugs in:

Parasite References

P. falciparum 70

BEST CLASSICAL SPORONTOCIDAL DRUGS: PYRIMETHAMINE, PROGUANIL ACTIVE BUT LESS PRACTICAL: 8-AMIN0QUIN0LINES

Purine. c»no| pyrimieíme. pr&cur&ors

PAB —> Folicocid—> Foli’o»c acid —4

^ ^ A - . VPunnes anoI pynmiolmes

Rollo

Fig. 1 P. berghei 6 3 /'&f/84 /11 2 2

Quinine •63/84/120/122' 55/63/84/122- Mepacrine

Proguanil <*122f + + +* ' — 55/63/84-----► Primaquine Triazine <4 8 4 ------<*122+ + + + + + + Pyrimethamine *4-55/63/84/122 Sulfon­ amides Resistance Fig. 3: P. berghei resistant to 4-amÍnoquÍnolÍneS. Inconstantly Cross resistance to other antimalarials. (The arrows reported resistance go from the substance to which the strain has been No resistance made resistant to the substance tested.) Hypersensitivity +■ + + + P. berghei Chloroquine „ Mepacrine

►

Resistance Fig. 4 : P. berghei resistant to the group Proguanil- Slight resistance Triazine-Pyrimethamine. Cross resistance to other Inconstantly antimalarials. (The arrows go from the substance to which reported resistance the strain has been made resistant to the substance tested.) No resistance P. berghei Chloroquine

Fig. 5: P. berghei resistant to the group Primaquine. Resistance Cross resistance to other antimalarials. (The arrows Slight resistance go from the substance to which the strain has been No resistance made resistant to the substance tested.) Hypersensitivity + + + + + ► Fig. 6: P. berghei resistant to the group Quinine Or Slight resistance ------► Mepacrine. Cross resistance to other antimalarials. No resistance ------(The arrows go from the substance to which the strain Slight hypersensitivityooooooo^. has been made resistant to the substance tested.) Hypersensitivity + ++++► P. gallinaceum Chloroquine ▲ Quinine Mepacrine

Resistance Slight resistance Inconstantly Fig. 7: P. gallinaceum cross resistance. reported resistance (The arrows go from the substance to which the strain has No resistance been made resistant to the substance tested.) Hypersensitivity + + + + + ► P. knowlesi Chloroquine

Quinine „ Mepacrine .

113 113- ...... 113 ......

______»»x lethamine -113- *■ Primaquine ~3t Pro- 113/115 guanil

Fig. 8: P. knowlesi cross resistant to the group Pyrimethamine- Proguanil. (The arrows go from the substance to which the strain has Slight resistance been made resistant to the substance tested.) No resistance P. cynomolgi Chloroquine

Quinine ,r Mepacrine •■r ▲ 105/114 1.04 9 0 ,.114 ... 126 ,104

4 I . #©••* *•* ••••** •

— 9 0 ' Primaquine I Pro-54# / V guanii Sulfon­ am ides,

Resistance Fig. 9: P. cynomolgi cross resistance. Inconstantly (The arrows go from the substance to which the strain has reported resistance been made resistant to the substance tested.) No resistance Maio - Junho, 19G7 Rev. Soc. Bras. Med. Trop.

Now to potentiation. The fact that as that of the usual sulfonamides. sulfadiazine and other p-aminobenzoic These two properties, rapid absorp­ competitors with antimalarial activity tion and slow elimination, together . are able to potentiate the action of with the good activity it has shown in proguanil against blood schizonts of the usual chemotherapeutic experi­ P. gallinaceum has been known sin- m ental tests (96, 128), have justified ce the work by Greenberg in 1949 (47, extensive clinicai trials with the subs­ 49-50). Proguanil and pyrimetha- tance in the common indications of mine do not potentiate each other the sulfonamides (1, 25, 64) , with es­ (101). Later on, it was proved that pecial attention to those in which sin- the same applies if the sulfonamide gle-dose treatment (e.g. meningococ- is replaced by a sulfone and/or if pro­ cal meningitis in epidemic developing guanil is replaced by pyrimethamine countries (39) and long-term treat- (4-5, 101). A similar potentiation has ments e.g. leprosy (3), trachoma in the meantime also been confirmed (40), systemic mycoses (74) are most in experimental and human toxo- indicated. plasmosis (34, 44, 59). In malaria, On the basis of the experience gai- however, there had until 1963 been ned during clinicai trials in the treat­ only a few tentative attem pts to test ment of about 15,000 cases (some 100 the potentiating effect between sul­ of them treated continuously for se- fonamides and pyrimethamine in veral years) it can be stated that the man (Hurly in 1959 (62); McGregor, tolerance of Fanasil is at least as good Williams and Goodwin in 1963, (80). as that of the most highly reputed In 1964, DeGowin and Powell (30) sulfonamides. The possibility of oral showed that 2,0 g sulfadiazine daily weekly administration makes Fanasil for 5 days gíven concurrently with 50 quite suitable for combined treatment mg pyrimethamine daily for 3 days with pyrimethamine. cured 5 out of 6 volunteers infected The activity of Fanasil in experi­ with the Malaya (Camp) strain of mental malaria has been studied by P. falciparum resistant to chloroqui- ne, hydroxy-chloroquine, quinacrine, Richards (94) (Table V ). Fanasil chlorguanide, and pyrimethamine. showed good antimalarial activity and Previous trials with the same doses a marked potentiation with pyrime­ thamine against sensitive strains as of sulfadiazine and pyrimethamine gi- well as against strains of P. gallina­ ven separately had not been suc- ceum and P. berghei resistant to py­ cessful. One month later, in December 1964, rimethamine, triazine or chloroqui- ne. The pyrimethamine-resistant Laing (67) reported on the first re- strain of P. gallinaceum was some­ suits of his study of the antimalarial what less sensitive to the potentiating effect of Fanasil (Ro 4-4393). This mixture (pyrimethamine + Fanasil) sulfonamide shows the longest period than the normal strain. However, the of elimination ever described in man. resistance factor was only 2 to 5, as It has a half-life of 100 to 200 hours. (Sulfadiazine: 17 hours). This per- compared with > 300 for pyrimetha­ mits therapeutically sufficient blood mine alone. leveis to be maintained by weekly ad- These results have been confirmed ministration of low doses, either oral- in their main lines by Brener (9). ly or parenterally. The slow elimina­ The optimum potentiating ratio in tion is not due to any intentional con- these chemotherapeutic studies se- ventional modification of the basic ems to be in the region of 10: 1 (Fa­ molecule (e. g. N, — acetylation) or nasil: pyrimethamine) but the ran­ to the pharmaceutical píesentation ge appears to be very broad. Prophy- (e. g. repository injection or late re- lactic single-dose treatment showed lease tablet), but to the intrinsic that Fanasil has the most prolonged structure of the basic molecule itself. activity among other long-acting sul­ Oral absorption of Fanasil is as rapid fonamides and DDS. 118 Rev. Soc. Bias. Med. Trop. Vol. I — N? 3

Fanasil (20 mg/kg x 7) and Fana­ P. falciparum. The results are sil - pyrimethamine (2.6 mg kg -j- shown in Table VII. The treat­ 0.004 mg/kg x 7) were also effective ment was considered to be a fail- against produced by P. gal­ ure in those cases where asexual linaceum sporozoites. Treated chicks parasitemia was present on the remained free from parasites for the seventh day of observation or duration of the experiment (35 days where therapeutic intervention of observation), whereas the Controls with another antimalarial drug died within 17 days (94) . It seerns was necessary in the interest of therefore that there may also be a the patient. After a single dose potentiation of the causai prophylac- of 1 g Fanasil given to 9 indivi­ tic effect. duais there was one failure. Clea- Treatment of acute malaria with rance of asexual parasitemia was Fanasil alone or combined with pyri­ somewhat slower than in African methamine : patients (average 3.1 days com­ pared with 2.3 days). Various a) P. falciparum'. Laing (68, 71, combinations of Fanasil (200 mg 72), working in Amani, Tanza- to 1 g) with pyrimethamine (25 nia, i.e. in an area where pyri­ to 50 mg) gave similar results methamine resistance is known in 53 patients (6 failures) with to occur, has reported the follo- an average duration of parasite­ wing results: mia of 2.2 days. Among the few A total of 105 “semi-immune” patients receiving the highest Bantu Africans seeking treat­ dose of 1 g Fanasil -I- 50 mg py­ ment for fever were treated with rimethamine there were no one dose of Fanasil (1 g) alone failures. 4 patients who had early (45 cases) or with one dose of recrudescences of parasitemia and febrile symptoms after treat­ 500 mg Fanasil in combination ment with chloroquine (1.5 — with 12.5 mg pyrimethamine (45 2.0 g orally over 3 to 4 days in cases) or with one dose of chloro- 3 adults and 0.280 g parenteral- quine (200 mg i.m. or 600 mg ly in a two year old girl) were orally) (15 cases) and thereafter also treated with a single dose a diagnosis of acute falciparum of Fanasil + pyrimethamine (1 malaria was made by means of g Fanasil + 25 mg pyrimethami­ parasite counts from thick blood ne for the adults and 250 mg films. The results are shown in Fanasil + 6,25 mg pyrimethami­ Table VI. In the group receiving ne for the child); three of the patients were “apparently cured” Fanasil + pyrimethamine, ase- and one (an adult) to whom py­ xual parasitemia was cleared in rimethamine was given 3 days 88% of the patients within 48 prior to Fanasil showed no res­ hours compared to only 30% in ponse to the dose of pyrimetha­ the group receiving Fanasil alo­ mine, whereas after Fanasil ne. In another experience, two scanty asexual parasitemia per- small children who had not res- sisted for 7 days. Among 36 pa­ ponded to 50 mg DDS did res- tients treated with 600 to 2,500 pond to 250 mg Fanasil alone mg chloroquine there were 11 (69) . failures . In an unpublished study car- In Bangkok, Harinasuta (52) gave Fanasil alone or in combi­ ried out recently in Malaya. nation with pyrimethamine or Laing (72) tried Fanasil alone chloroquine to 66 patients (adul­ or with pyrimethamine in 62 ts) with recrudescences after “semi-immune” patients suffer- chloroquine-resistant acute P. ing from acute malaria due to falciparum m alaria. The preli- Table V

The antlmalarial activity against drug sensitive and d r u g resistant strains of P. gallinaceum and P. berghei* Results expressed as the levei of drug which reduoes the

parasitemia to 50# of the untreated Controls (BDcjq) (Richards^*)

ED50 (mg/kg x 7 orally)

Drug P. gallinaceum P. berghei

Pyrime thamine Pyr ime thamine Triazine Chloroquine Chloroquine sensitive resistant resistant sensitive resistant < ' i ' strain > 300 X > 25 x strain > 12 x

Pyrimethamine 0.03 > 10 - 0.15 0 . 1 5

Sulphorthomidine 20.0 25 25 1.0 1.0

Sulphorthomidine 2.6 + 5 + 0.1 + 0.1 + + pyrimethamine 0 . 0 0 4 0.02 0 . 0 1 2 5 0.0125

Chloroquine - - - 8.0 > 100.0 , toxic T able VI

Average duration of asexual parasitaemia of P. falciparum and fever after 71 72 treatment with Fanasil alone and in combination with pyrimethamine (Laing, Tanzania ’ )

Drug No. of Pats. Failures* Mean duratic>n in days

Parasitaemia Fever

Fanasil ** 1 g 45 7 2.3 2 (19 cases)

Fanasil 500 mg *** 45 0 Pyrimethamine 12.5 mg 1.8 1.5 ( 9 cases)

Chloroquine 200 mg i.m. or 15 0 1.7 - 600 mg orally

* Parasites still present in blood films on the 7th day or other drug required before the 7th day. ** Children up to 11 years received 250 to 750 mg *** Children up to 11 years received 125 to 375 mg T able VIII Effect of Fanasil given alone or in combination with Daraprim or chloroquine C p to adult patients--wi-th ehloroquine-resistant falciparum inalaria (Harinasuta, Thailand )

Drug regimen No. of Successes Failures Average duration of parasitemia (single dose)* patients + fever in davs (excl. failures) treated cured cleared** C.T.E. P.T.E. Parasitemia Fever

Fanasil 1 g 16 9 2 - 5 5 2.1

Fanasil 1.5 g 7 2 2 2 1 4.6 2.3 Fanasil 250 mg + 6 4 1 1 - 4 2 Daraprim 12.5 mg

Fanasil 250 mg + 15 10 - 2 3 3.6 1.7 Daraprim 25 mg

Fanasil 0.5 g + 5 1 2 2 - 4.1 0.6 Daraprim 25 mg

Fanasil 1 g + 17 13 - 2 2 4 1.5 Chloroquine 1.5 g (in 3 days)

* except for chloroquine ** with a follow-up of less than 28 days

C.T.E. = complete temporary effect (clearance of asexual parasitemia with subsequent relapse) P.T.E. * partial temporary effect (reduction not abolition of asexual parasitemia) Maio - Junho, 1967 Rev. Soc. Bros. Med. Trop. 123

minary results are shown in Ta­ tes disappeared from the blood ble VIII. On the basis of clinicai in 4 to 6 days and the gametocy­ response and duration of para- tes in about a month. sitemia, the best results were ob- Almeida, Brazil, (2) has repor­ tained with the following com- ted on the preliminary results of binations: A) 1 g Fanasil (sin­ an extensive study being carried gle dose) + 1.5 g chloroquine out in cases of spontaneous ma­ in three days); B) 0.5 g Fana­ laria. The patients are followed sil + 25 mg pyrimethamine in a up for 6 days after receiving one single dose. The latter has the of the three following treat- practical advantage of being a ments: Group A) 10 mg/kg one-dose therapy. Since dura­ chloroquine, 5 days later 10 tion of parasitemia is longer than mg kg chloroquine and 5 mg that seen after chloroquine in kg chloroquine on each of the 2 chloroquine-sensi,tive cases, fur- following days (total dose 30 ther trials are being carried out mg/ kg in 8 days). Group B) 40 with higher doses of the combi­ mg/kg chloroquine in 4 days. nation Fanasil + pyrimetha­ Group C) 1 g Fanasil and 50 mg mine. pyrimethamine on the first day Sensitivity to chemotherapy of and 0,5 g Fanasil on the follow­ seven strains of P. falciparum ing day. According to the preli­ found in four Brazilian regions, minary results (197 courses of in patients who did not respond treatment in 178 patients fol­ satisfactorily to chloroquine, was lowed), some cases of the groups studied by Lopes and Rodrigues A and B have shown recrudes- da Silva (75) in 25 neurosyphili- cences during the follow-up pe- tic patient with blood-induced riod. In the group C (14 cases malaria. Ali seven strains show already observed over 60 days) ed resistance to the standard 4 cases became negative during “field—test” dose (10 me/ke of the first day of treatment and chloroquine recomended by WHO the other 10 cases during the for preliminary selection of sus- second one. Ali of them re- p e c t e d chloroquine-resistant mained negative over the follow- strain s). Three of the seven up period. strains turned out to be only Peringle and Lane (89), Tan­ partially chloroquine - resistant, zania, have reported on the re­ since parasitemia disappeared sults obtained with 250 mg Fa­ nasil in 9 schoolchildren who after a higher dose of chloroqui­ developed one or two clinicai ne (3 g in 3 days). The other four fits of falciparum malaria three strains were considered as fully to six months after the injec- resistant to chloroquine; two of tion of the repository antimala­ them were also resistant to pyri­ rials cycloguanil pamoate, or methamine, and at least partial­ DADDS, or both (Table X). Bv ly, to quinine. These two last the fourth day after the dose of strains (PoL, and Po::), i. e., those Fanasil trophozoites had disap­ fully or partially resistant to the peared from the blood in ali three above mentioned major an­ cases. b) P. vivax. Confirming the results timalarials, were sensitive to Fa­ obtained by previous workers nasil combined with pyrimetha­ with older sulfonamides, Laing mine. As shown in Table IX, the in Malaya also found P. vivax to therapeutic response (8 cases), be less sensitive to Fanasil than however, took place rather slow- P. falciparum (Table VII) (72). ly. Clinicai response was achie- Out of 13 patients with acute ved in 4 to 8 days, the trophozoi- vivax malaria treated with 1 g. T able IX

Therapeutlo response to the assoclatlon

Ro 4 - 4 3 9 3 + Pyrimethamine

(Lopes and da Silva, Brazil*^)

Ho* of Ro 4 - 4 3 9 3 / 2 Clinicai Parasitemia patlent + pyrimethamine F39POZ1SG Pft Pfg

500 mg + 50 mg 18 5 d 5 d 30 d 5 d

13 Idem 5 d 4 d 30 d

21 Idem 6 d 5 d 28 d

1 g + 50 mg 8 5 d' 4 d 11 d* 3 d

25 Idem 8 d 5 d 24 d*

26 Idem 4 d 4 d 8 d*

27 Idem 5 d 5 d 7 d*

19 Idem 5 d 6 d 17 d*

* under observation

. I Í ; Pft = trophozoites (P. falciparum) Pfg = gametocytes (P. falciparum) d = days Table X

Results obtained with a single dose of 250 mg Fanasil'in 7 patients having developed clinicai falciparum malaria 3 to 6 months after the injection of a repository anti­ malarial (cycloguanyl pamoate, diacetyldiaminodiphenylsulfone or both)

(Pringle and Lane, Tanzania )

Subject Age in Repository Dose of Interval after Trophozoite counts per cu. mm. on code years drug rep.drug injection of post-treatment .days numberj in mg/kg. rep. drug: Pre-treatment: Day 1 Day 2 Day 3 Day 4

BB/10 12 Cl-501 10.8 D + 85 7.440 Neg. Neg. Neg. Neg.

AB/ 4 9 II 12.4 D + 137 17.200 65 Neg. Neg. Neg. AB/21 10 If 11.8 D + 179 80.360 32 112 48 Neg.

AY/27 8 Cl-556 8.4 D + 148 8.400 14.520 Neg. Neg. Neg. II 11 II II D + 199 2.880 3J60 Neg. Neg. Neg. AY/17 8 It 7.0 D + 200 4 4.560 4800 2.500 3.240 Neg.

AG/ 5 9 Cl-564 14.3 D + 140 8.800 820 Neg. Neg. Neg. II It II II D + 196 21.600 L640 Neg. Neg. Neg. AO/26 8 II 13.2 D + 172 27.500 600 Neg. Neg. Neg. 126 Rev. Soc. Bras. Med. Trop. Vol. 1 — N° 3

Fanasil, 5 were failures. Out of gle and Lane (89) had the op- 14 treated with Fanasil + pyri­ portunity of testing the sup­ methamine 2 were failures. Ho- pressive effect of Fanasil and wever, on the average the para­ Dapsone on break-through para- sitemia disappeared as quickly sitemias among children pre- as in falciparum cases that res- viously injected with one of the ponded. Higher doses should above mentioned repository an- be tried in view of the fact that timalarial agents. These subs- another investigator in Indoné­ tances had been administered sia has obtained preliminary re­ during a drug trial conducted 5 sults in P. vivax which are at months previously. As shown least as good as those he obtai­ iin Table XII a single dose of ned in P. falciparum (61) . 100 mg Fanasil was first given c) P. malariae and P. ovale. The to patients of the and scanty material available on sulfone groups. Out of 34 tro- these two species seems to indi- phozoite carriers, only two had cate that they respond worse to scanty parasitemia one week la- Fanasil than P. falciparum, but ter, whereas 13 were again po­ that the association Fanasil + sitive after one month. At that pyrimethamine is active. time the patients of these two groups received one 100 mg dose Suppressive treatment with Fanasil of Dapsone which failed to sup- alone and combined with pyri­ press parasitemia in 2 cases. methamine. Two and a half months later, the three groups (biguanide, a) P. falciparum. The effect of sin­ sulfone and combined) were gi­ gle and weekly administration ven either 100 mg Fanasil (68 of Fanasil, pyrimethamine, and patients) or 100 mg Dapsone their combination on pariasite- (54 patien ts). Fifty days later mia due to P. falciparum in the same patients received 50 schoolchildren was extensively mg Fanasil or Dapsone. From studied by Laing in Tanzania the overall results it appears (66, 72). The results are sum- that Fanasil was the more ef­ marized in Table XI. It seems fective drug in suppressing such that in schoolchildren doses as break-through parasitemias. low as 125 mg Fanasil weekly Shute and Dowling (110) com- were capable of suppressing pared the suppressive action of Fanasil and chloroquine on pa­ asymptomatic asexual parasite­ rasitemia in schoolchildren li­ mia in the great majority but ving in the Western region of Ni­ not in ali cases. No failures géria where malaria is holoen­ were seen when this dose (or demic . As shown in Table XIII, even less) was combined with the children of each of three 6.25 or 12.5 mg pyrimethamine. large schools received one of the Pyrimethamine alone was not following drug regimens: Fana­ effective since 38% and 18% of sil 500 mg once a week for 4 the children still had asexual weeks, Fanasil 500 mg as a sin­ parasitemia 7 days after one gle dose, or chloroquine 300 mg dose of 25 and 75 mg respecti- as a single dose. No treatment was given in two smaller schools vely. Even after 4 to 6 weekly where the children were consi- doses of 25 mg pyrimethamine, dered as Controls. Blood sur- 27% of the children were still veys (thick blood films) were positive. carried out before the beginning In the same holoendemic area of the trials and at weekly in- in Northeastern Tanzania, Prin- tervals for 4 weeks thereafter. Table XI

Effect of Fanasil and pyrimethamine given alone or in combination against pyrimethamine-resistant Plasmodium falciparum in semi- immune schoolchildren with a pre-treatment parasite incidence of over 255^ (Laing, Xanzania^*^ )

No. of children Dosace No. of children examined i»osage with trophozoites Fanasil alone 176 500 mg/week for 4-6 weeks 2 140 250 mg/week for 8 weeks 1 (after 2 doses) 0 (after 4 doses) 2 (after 8 doses) 126 125 mg x 1 0 (1 P. ovale) 37 100 mg x 1 4 36 75 mg x 1 1 35 50 mg x 1 2 33 25 mg x 1 3 Fanasil (F) + pvrimethamine (P) 178 F 500 mg + P 25 mg once 0 weekly for 4-6 weeks 159 F 250 mg + P 12.5 mg/week 0 (after 2 doses) for 8 weeks 1 (after 4 doses) 0 (after 6 & 8 d.) 125 F 125 mg + P 12.5 mg x 1 0 54 F 100 mg + P 12.5 mg x 1 0 83 F 7 5 mg + P 12.5 m g x l 0 39 F 50 mg + P 12.5 mg x 1 2 37 F 25 mg + P 12.5 mg x 1 4 39 F 125 mg + P 6.25 mg x 1 0 29 F 100 mg + P 6.25 mg x 1 0 33 F 75 mg + P 6.25 mg x 1 1 Pvrimethamine alone 133 12.5 mg for 8 weeks 17 (after 2 doses) 19 (after 4 doses) 17 (after 6 doses) 16 (after 8 doses) 122 75 mg x 1 22 (18/.) 123 25 mg x 1 47 (38/.) 684 25 mg/week for 4-6 weeks 184 (27?í) Untreated 67 48 (71*0 Table XII

Response of asymptomatic parasitemias occurring among children (previously injectedL with a repository antimalarial) to single doses of Fanasil or Dapsone (Pringle and Lane, Tanzania®^)

Patients with trophozoites, of P. falciparum Drug and Type of re­ Days since No. of before and after thõ "super-treatment" dose pository drug injection patients Before treatment One week later

Biguanide 57 16 1 * Fanasil 150 100 mg Sulfone 53 18 1 *

Dapsone Biguanide 59 6 0 182 100 mg Sulfone 59 7 2

Biguanide 28 0 Fanasil 13 Sulfone 22 10 100 mg 254 0 Combined 18 11 0 Biguanide 6 1 Dapsone 13 Sulfone 21 8 100 mg 254 3 Combined 20 6 0

Biguanide 13 0 Fanasil 29 Sulfone 22 10 0 50 mg 505 Combined 18 11 0

Biguanide 13 6 0 Dapsone Sulfone 305 24 10 1 50 mg Combined 19 10 0

* in both of these cases the parasite density was extremely low Maio - Junho, 1967 Rev. Soc. Bros. Med. Trop. 129

The untreated Controls showed sistence of P. ovale in 6 school­ continuing falciparum parasite­ children treated with Fanasil. mia in 69 to 81% of the cases In 3 further cases the trophozoi­ throughout the trial. Both re- tes apparently emerged during gimens of Fanasil were found to suppressive treatment with Fa­ be highly effective against ase­ nasil. In Indonésia, clearance xual P. falciparum parasitemia of P. vivax parasitemia seems to as from the first week when ali have been rather slow, complete cases were negative. In the Fa­ clearance having been achieved nasil groups, the highest inci- 3 weeks after the beginning of dence of children with tropho- treatment with Fanasil, with or zoites was 2% after 4 weeks (in without pyrimethamine, given as the single dose group), whereas a single dose or once weekly. in the chloroquine group the in- cidence of positive cases was 5'/ Gametocytocidal effect: According after one week and progressively to the findings reported by Shute and increasing to 16% after 4 weeks. Dowling (110) and by Laing (66, 72), b) P. malariae. Shute and Dow- Fanasil has actually no gametocyto­ ling (110) also registered quite a cidal effects, the slow disapearance of high pre-treatment incidence of sexual forms of P. falcivarum being asexual parasitemia due to P . the result M the schizonticidal action malariae during the surveys in of the drug. the above mentioned Nigerian schools. The rates of positive Effect on sporogony: Investigations cases before and after treatment were carried out by Laing (70, 72) to are given on the extreme right determine the effect of Fanasil alone of Table XIII which shows a rate and combined with pyrimethamine of 10 to 15 % prior to treatment, on falciparum sporogony. Batches of increasing to 19Çv after 4 weeks laboratory-bred Anopheles gambiae in the control group. This ta­ were fed on patients with sexual pa­ ble also shows that the effect of rasitemia after treament. Ali sur- chloroquine on P. malariae was viving mosquitoes were negative after entirely satisfactory and that having fed on 2 patients previously both regimens of Fanasil were treated with 500 mg Fanasil + 12.5 almost as effective as chloro­ mg pyrimethamine. The same result quine . was obtained in a further 2 patients Recent (unpublished) work after the combination of 500 mg Fa­ carried out in Indonésia (61) in- nasil and 6.25 mg pyrimethamine. dicates that Fanasil given alone However, when a 1 g dose of Fanasil or together with pyrimethamine alone was given to a patient on two is capable of completely sup­ occasions, a significant number of pressing P. malariae parasitemia mosquitoes were found to be positive by the second week after the after each dose. Consequently Fa­ first dose. Confirmatory trials nasil alone does not seem to affect are bpihg undertaken. normal falcivarum sporogony in mos­ c) P. vivax, and P. ovale. The num ­ quitoes. When given together with ber of Cases treated with Fana­ a small dose of pyrimethamine, which sil is too small to permit evalua- may be insufficient in itself, there tion of the results. In Africa, appears to be potentiation of the spo­ Laing (72) observed the emer- rontocidal effect of the latter. In ex­ gence of P. ovale in 2 patients perimental malaria (P. gallinaceum) having received weekly doses of such a potentiation has already been 250 mg Fanasil. In another described by Ramakrishnan et al. case trophozoites persisted after (91) for DDS, although given by it­ one dose of 1 g Fanasil . Shute self this substance did not show any and Dowling (110) observed per- sporontocidal effect. Table XIII

Effect of Panas11 and chloroquine on asexual parasitemia in African schoolchildren of 6 to 14 years (control group 6 to 11 years) (Shute and Dowling,Nigeria )

No. of P. falciparum P. malariae Drug and dosage Blood surveys patients examined Positive Rate f» Positive Rate ?£

Fanasil 500 mg Before treatment 209 161 77 21 10 once a week for after: 1 week 195 0 5 3 4 weeks 2 weeks 194 0 mm 0 3 weeks 189 1 0.5 0 4 weeks 185 1 0 0.5 N

Fanasil 500 mg Before treatment 261 175 67 39 15 single dose after: 1 week 240 0 - 2 1 2 weeks 237 2 1 0 - 3 weeks 238 1 0.5 1 0.5 4 weeks 233 4 2 0 -

Chloroquine Before treatment 248 185 75 25 10

300 mg after: 1 week 222 5 2 0 - single dose 2 weeks 216 8 4 0 -

3 weeks 223 21 9 0 - 4 weeks 147 24 16 0 -

Untreated Before trial 78 60 77 10 13 Controls after: 1 week 89 61 69 11 12 2 weeks 76 56 74 13 17 3 weeks 81 62 76 7 9 4 weeks 84 68 81 16 19 Maio - Junho, 1967 Rov. Soc. Bros. Med. Trop. 131

S U M M A R Y

Review of the early literature as well as more recent results show that sulfonamides possess a distinct antimalarial activity. However, when give alone, their action is less markeã anã slower than that of the antimalarials commonly used in the treatment of the acute attack. Combinations with pyrimethamine proviáe better results, even in cases of pyrimethamine anã chloroquine resistance. This warrants further investigations in an attempt to ãevelop a therapeutic agent suitable for the treatment of such resistant cases. It may also be possible with an appropriate combination of pyrimethamine with a sulfonamide to achieve a satisfactory method for suppressive treatment both in areas with and without pyrimethamine resistance. Three main points must still be carefully studied: 1) the risk of developing malaria resistance against one or both of the components of the combination. 2) The risk of developing bacterial resistance to sulfonamides if these substances are used on a large scale in too low doses. It seems indeeâ that antimalarial effect with the combination of sufonamides +- pyrimethamine can be obtained with doses of sulfonamides which are below those usually employed in bacterial diseases. Since the range of the ratios providing potentiation is rather large, only ratios of the combi­ nation sulfonamides: pyrimethamine should be chosen in which an antfbacterial :;ulfonamidemia is guaranteed. 3) It goes without sayinq that, although both pyrimethamine and modem sulfonamides, when given by themselves, have proveã tc possess a large margin of safety, long term administration of their combi­ nation should be careful studied from the point of view of possible side effects. Substantial evidence has already been produced to show that the long acting sulfonamide Fanasil (Ro 4-4393) given once or once weekly possesses marked schizonticidal activity against P. falciparum. Although its action is slower than that of 4-aminoquinolines, it may be useful as a second choice drug in semi-immune subjects for the therapy of falciparum malaria. Prelimi- nary results show that, when combined with pyrimethamine, Fanasil is highly cffective in suppressing fever and asexual parasitemia due to P. falciparum. Single doses of 1 g Fanasil together with 50 mg pyrimethamine seem to be adequate for the treatment of acute falciparum malaria in semi-immune pa­ tients. The onset of action of the combination is much more rapid than that of the single components. Weekly doses of 500 mg Fanasil and 25 mg pyrime­ thamine appear to provide satisfactory suppressive effects against P . falciparum at least in East Africa. This combination is active on strains which do not respond satisfactorily to the standard doses of pyrimethamine and/or chloro­ quine and seems to have a satisfactory sporontocidal effect. Preliminary results indicate that Fanasil alone cannot be recommended for use against the other human malaria parasites. The combination with pyrime­ thamine appears to be much more effective. East African strains of P. malariae seem to respond better to the combination than do Malayan strains of P. vivax but further trials are required before definite assessment can be made. Fanasil by itself has no gametocytocidal or sporontocidal action but seems to potentiate the effect of pyrimethamine at least on sporogony of P. falciparum.

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