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The Use of Long Acting Sulfonamides. Alone Or with Pyrimethamine, in Malaria (With Special Reference to Sulformetoxine)

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The Use of Long Acting Sulfonamides. Alone Or with Pyrimethamine, in Malaria (With Special Reference to Sulformetoxine) THE USE OF LONG ACTING SULFONAMIDES. ALONE OR WITH PYRIMETHAMINE, 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, chloroquine and perhaps with prac^ical aims was almost dropp- even quinine, 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 sulfonamide 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. proguanil and sulfadiazine (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, biguanides 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 MEPACRINE, 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.
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