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Sulfadoxine-pyrimethamine for the treatment of malaria
556 TRANSACTIONS
OF THE ROYAL
1Correspondence
SOCIETY
OF TROPICAL
MEDICINE
AND
1
Toxocara
canis and pregnancy in mice The statement of Dr Akao and his colleagues (1990: Transactions, 84, 724) that no study before their own hasexaminedthe effect of Toxocara canis infection on pregnancy and its outcome in the rodent host is somewhatmisleading.It is correct to statethat there had beenno publishedstudy beforetheir own which reportedthe effect of T. canis infection on mouselitter size. However, the effect of this parasiteon pregnant mice has been investigated by Pike (1960: Experimental Parasitology,, 9, 223-232) and Oshima (1961:Journal of Parasztology, 47,65&660). Lee et al. (1976:3ownal of Parasitology, 62,460-465) extended thesestudiesand found that, in miceinfected for one week but not 2 weeks before gestation,larvae were present in the uterus, but not in the placenta or foetus. In mice infected during pregnancy, larvae were found in the uterus and placentafrom the 9th day and in the foetusfrom the 1lth day of pregnancy. Lee andhis co-workers(lot. cit.) suggested that in the pregnant mousethe migration of T. canis larvae is influencedby the developmentalstageof the placenta. Myra A. Arnott John Hay Deoartment of Pharmacy Letcester PO&technic P-0. Box 143 Leicester, LED1 9BH UK
12 November 1990
Toxocara canis and pregnancy: a reply Drs Arnott & Hay point out that the effect of litter sizeof pregnantmice infected with Toxocara canis has previously been investigated by Pike (1960: Experimental Parasitology, 9, 22>232), Oshima (1961: 3ournal of Parasitology, 47, 656-660) and Lee et al. (1976: 3ourd of Parasitology, 62, 46U65). They misreadour paper. We put emphasison the decrease in the numberof miceborn to a mother infectedwith T. canis before gestationcommenced.In the papers cited by Arnott & Hay, no information was given about the numbers of litters born to mice infected with T. canis, so one cannot assesswhether the authors had noticed a decreasein litter size. In the work reported by Lee et al. (Zoc. cit.) no larvaewere found in the uterus, placentaor foetusof mice infected more than 2 weeks before becoming nreanant. However, we found somelarvae in both uterus and placenta-ofmice infected with T. canis 4 weeksbeforematina (unpublisheddata). The reasons for this difference are not known, but .we supposeit might be attributable to the method used to recover larvae from the organs. Lee and colleaguesused Bearmann’sapparatus, while we used the method described by Parsons& Grieve (1990: 3ournd of Parasitology,-
76, 53-58).
We have noticed no decreasein litter size in mice infected with Trichinella spiarlis (unpublisheddata), so we think that the decreasewe reported with mice infected with T. canis wasrelatedto the possibility of
HYGIENE
(1991)
85,
CORRESPONDENCE
transplacentalinfection by larvaeof the latter species. Lee et al. (lot. cit.) observedrupture of the labyrinth wall by larvae of T. canis, and suggestedthat this might leadto abortionin the early stageof pregnancy. Further pathological studies are under way in our laboratory. Nobuaki Akao Department of Parasitology School of Medicine Kamazawa University 13-I Takara-machi Zshikawa Jam
1 February 1991
Sulfadoxine-pyrimethamine for the treatment of malaria ProfessorSalakoand his colleagues(1990: Transactions, 85, 641-643)showthat intramuscularadministration of sulfadoxine-pyrimethamine(S-P) to Nigerian adults with uncomplicatedfalciparum malaria (only 54% of whom were febrile) is associated with a mean fever clearance time of l-9 d (standard deviation+l*6) and parasiteclearancetime of 2-O d (+0*7), and that these results are similar to the resnonseto a higher dose of oral S-P. Thev then compare this with oral chloroquine treatment of a group of patients who were considerably younger (mean age 4 years), more symptomatic (81% were febrile), and had stgnificantly higher parasitaemias. This doesnot seemto be a fair comparison.However, evenif the patient groupshadbeenwell matched,and sulfadoxine-pyrimethaminehad producedmorerapid clearanceof parasitaemia,it does not follow from theseresultsin oligosymptomatic,ambulant, almost immuneadultsthat intramuscularS-P ‘deservesto be more widely usedas an alternative to intramuscular chloroquine’ or that ‘There is therefore no justification for witholding intramuscular S-P from patients with acute falciparum malaria requiring treatment with parenteral drug’. Although it is generally assumedthat drugs which produce rapid parasite clearancewill be more efficaciousin severemalaria, there is no convincing evidencethat this is true for the most important measureof therapeutic responsei.e., survival. Parasiteclearanceis widely usedas a measureof the therapeutic responsein malariabut it is worth asking: why should rapid removal of ring-form infected erythrocytes from the circulation save life? It is the mature parasitesin cytoadherent erythrocytes sequesteredin the microvasculatureof vital organsthat are thought to causepathology in malaria.Thus it is the parasiteswe cannotsee,not the oneswe cansee,i.e. it is the current asexualcycle, not the next, which may kill the patient (White & Krishna, 1989:Transactions, 83, 767-777). Obviously, the dynamicsand stage-specificityof antimalarial action, as well as the pharmacokineticpropertiesof the drug, are critical determinants of therapeutic outcomebut as yet we do not know the relative importance of these factors, nor have they been adequately characterized. Professor Salako and his colleaguesrightly recommendfurther carefully monitored studiesbefore advocatingroutine useof intramuscularS-P in cerebralmalaria(a recommendation
557
that seemshard to reconcile with their earlier statements).A great deal more evidenceis certainly required, and eventually this must be obtainedfrom severely ill children, not oligosymptomaticimmune adults. Finally, on a separatepoint, we recommended intramuscularchloroquineregimensof 3.5 mg base/ kg six-hourly or 2.5 mg base/kgfour-hourly in severe chloroquinesensitivemalaria(White et al., 1988:New England
3ournal
of Medicine,
319, 1493-1500),
rwt
3.5 mgibasekgkghr-hourly asstatedin the introduction of ProfessorSalako’spaper. Nicholas J. White Wellcome-Mahidol Universihhoxford Tropical Medicine Research-Probamme Facultv of Troika1 Medicine Mahi& bziv&ity 42016 Rajvithi Road Batl$&ok& 10400 22 November 1990
Sulfadoxine-pyrimethamine for the treatment of malaria: a reply In reply to Dr N. J. White’s letter [above], I should like to point out that intramuscular sulfadoxinepyrimethamineis widely availablebut is very rarely used.We gavethe reasonfor this stateof affairsin our paper and thought a re-evaluationwas called for (a similar re-evalu&ion by us of chloroquine in a series of papersfrom 1979helned in oreventine that verv useful drug from being prematurely dumped in Africa). We felt that re-evaluation should start, on ethical grounds,in patientsnot in immediatedanger of their life-adult Africans. If it turns out not to be effective and acceptablein that group, there would clearly be no justification for testing it in children whoseillnesscan progressrapidly wi& inappropriate therapy. If it were found to be usefulin adults then a trial in children could be justified. This is precisely what we have done. Following our demonstrationof satisfactory effect in adults, we conducted another trial in children, the results of which will soon be published. We now think there is iustification for cautiousevaluationin severeand complicatedmalaria, which we are soon to embark upon. Department of Pharmacology College of Medicine University of Zbadan Zbadan Nigeria
Fntagous
Lateef A. Salako and Therapeutics
beenobservedalsoin casesof visceralleishmaniasis. As indicated by ProfessorsRioux and Lanotte, the strains producing the cutaneous forms are more commonly enzymatic variants of MON-1, and the zymodeme variants isolated from skin lesions are seldomor never presentin visceral isolates.Finally, thev indicated that the so-calledL. chagasi. from visceralcasesin 6 Latin American count&, including Honduras,alsocorrespondedto their zymodeme MON-1. The questionthen arises,whether the presenceof cutaneousleishmaniasisdue to L. infantum, in a certain geographicalarea,dependson the strainof the parasiteinvolved, or on other factors associated with the human host, or both. We pointed out, as a characteristicof our focus, that no visceral clinical casehas ever been observedin CostaRica. On the other hand, a recent report (Ponce et al., 1991: Lancer, 337, 67-70) described17 atypical cutaneous cases,produced bv L. donovani chaaasi. identical to thosefrom CostaRica; theseoccur&d in an areaof visceralleishmaniasis in Honduras.lessthan 400 km from our focus. Assuming that the parasite is the same,how can we explain this important difference between the 2 foci? We know that Costa Rica has better sanitary conditions,with a lower child mortality rate and a lower malnutrition index, than Honduras. A prospective study made by ProfessorR. Badar6and his group in Bahia, Brazil (Badar6et al., 1986: Journal of Infectious Diseases, 154, 639-649; Cerfet al., 1987:bid., 156, 1030-1033)suggested that malnutrition and concomitantinfectious diseases, at an early age, are 2 important risk factors in the acquisition of the classicalpicture of visceral leishmaniasis.In the absenceof theserisk factors, a good immunologicalresponsemay determine that asymptomatic casesevolve to spontaneouscure (Badar6et al., 1986: 3ownal of Infectious Diseases, 154, 10031011). Perhapsthis favourableresponsemay alsolimit the diseaseexclusively to a cutaneousform, asin the CostaRica casesand in someHonduran ones. Since the Central American cutaneous picture is not observedin Brazil, we believe that particular strain characteristicscould also be involved in the final clinical picture and its resolution. In relation to the decline of visceral leishmaniasis during recent years in Italy, Bettini et al. (1983: Annales
27 December 1990
leishmaniasis and Leishmania
in-
ProfessorsRioux and Lanotte (1990: Transactions, 84, 898)referred to our Short Report (1989: Transactions, 83? 786) on a focus of atypical cutaneous leishmamasisproduced by Leishmania infanturn in north-westCostaRica. After our report appeared,the group from Montpellier sentme a seriesof paperson their valuable contributions regarding the various asnectsof a cutaneoustvne of leishmaniasis due to L. infanturn occurring in- several countries of the Mediterranean basin. Thev reoorted (Rioux et al.. 1986:Transactions, 80, looklob5) that,‘ in France, at least 5 different zymodemesof the parasite could produce this picture and one of them (MON-1) had
de Parasitologic
Hum&u
et Comparie,
58,
539-547)statedthat improvementof nutrition in the post-warperiod ‘might be one of the factors inherent to the decreaseof overt visceralleishmaniasis cases...’ Whether or not the Honduran and Costa Rican strainsof the parasiteareidentical, and factorsrelated to the human host and to the local conditions are responsiblefor the absenceof the classicalvisceral picture in the latter, remainsto be demonstrated. PZET Escuela de Medicina Universidad National Heredia, Costa Rica
Rodrigo
Zeled6n
Veterkria 1 April 1991
Mebendazole in giardial infections: co&ation of the failure of this treatment We havereadwith interestthe controversybetween Dr Noori S. Al-Waili and Drs J. Gasconand M.
OF THE ROYAL
1Correspondence
SOCIETY
OF TROPICAL
MEDICINE
AND
1
Toxocara
canis and pregnancy in mice The statement of Dr Akao and his colleagues (1990: Transactions, 84, 724) that no study before their own hasexaminedthe effect of Toxocara canis infection on pregnancy and its outcome in the rodent host is somewhatmisleading.It is correct to statethat there had beenno publishedstudy beforetheir own which reportedthe effect of T. canis infection on mouselitter size. However, the effect of this parasiteon pregnant mice has been investigated by Pike (1960: Experimental Parasitology,, 9, 223-232) and Oshima (1961:Journal of Parasztology, 47,65&660). Lee et al. (1976:3ownal of Parasitology, 62,460-465) extended thesestudiesand found that, in miceinfected for one week but not 2 weeks before gestation,larvae were present in the uterus, but not in the placenta or foetus. In mice infected during pregnancy, larvae were found in the uterus and placentafrom the 9th day and in the foetusfrom the 1lth day of pregnancy. Lee andhis co-workers(lot. cit.) suggested that in the pregnant mousethe migration of T. canis larvae is influencedby the developmentalstageof the placenta. Myra A. Arnott John Hay Deoartment of Pharmacy Letcester PO&technic P-0. Box 143 Leicester, LED1 9BH UK
12 November 1990
Toxocara canis and pregnancy: a reply Drs Arnott & Hay point out that the effect of litter sizeof pregnantmice infected with Toxocara canis has previously been investigated by Pike (1960: Experimental Parasitology, 9, 22>232), Oshima (1961: 3ournal of Parasitology, 47, 656-660) and Lee et al. (1976: 3ourd of Parasitology, 62, 46U65). They misreadour paper. We put emphasison the decrease in the numberof miceborn to a mother infectedwith T. canis before gestationcommenced.In the papers cited by Arnott & Hay, no information was given about the numbers of litters born to mice infected with T. canis, so one cannot assesswhether the authors had noticed a decreasein litter size. In the work reported by Lee et al. (Zoc. cit.) no larvaewere found in the uterus, placentaor foetusof mice infected more than 2 weeks before becoming nreanant. However, we found somelarvae in both uterus and placenta-ofmice infected with T. canis 4 weeksbeforematina (unpublisheddata). The reasons for this difference are not known, but .we supposeit might be attributable to the method used to recover larvae from the organs. Lee and colleaguesused Bearmann’sapparatus, while we used the method described by Parsons& Grieve (1990: 3ournd of Parasitology,-
76, 53-58).
We have noticed no decreasein litter size in mice infected with Trichinella spiarlis (unpublisheddata), so we think that the decreasewe reported with mice infected with T. canis wasrelatedto the possibility of
HYGIENE
(1991)
85,
CORRESPONDENCE
transplacentalinfection by larvaeof the latter species. Lee et al. (lot. cit.) observedrupture of the labyrinth wall by larvae of T. canis, and suggestedthat this might leadto abortionin the early stageof pregnancy. Further pathological studies are under way in our laboratory. Nobuaki Akao Department of Parasitology School of Medicine Kamazawa University 13-I Takara-machi Zshikawa Jam
1 February 1991
Sulfadoxine-pyrimethamine for the treatment of malaria ProfessorSalakoand his colleagues(1990: Transactions, 85, 641-643)showthat intramuscularadministration of sulfadoxine-pyrimethamine(S-P) to Nigerian adults with uncomplicatedfalciparum malaria (only 54% of whom were febrile) is associated with a mean fever clearance time of l-9 d (standard deviation+l*6) and parasiteclearancetime of 2-O d (+0*7), and that these results are similar to the resnonseto a higher dose of oral S-P. Thev then compare this with oral chloroquine treatment of a group of patients who were considerably younger (mean age 4 years), more symptomatic (81% were febrile), and had stgnificantly higher parasitaemias. This doesnot seemto be a fair comparison.However, evenif the patient groupshadbeenwell matched,and sulfadoxine-pyrimethaminehad producedmorerapid clearanceof parasitaemia,it does not follow from theseresultsin oligosymptomatic,ambulant, almost immuneadultsthat intramuscularS-P ‘deservesto be more widely usedas an alternative to intramuscular chloroquine’ or that ‘There is therefore no justification for witholding intramuscular S-P from patients with acute falciparum malaria requiring treatment with parenteral drug’. Although it is generally assumedthat drugs which produce rapid parasite clearancewill be more efficaciousin severemalaria, there is no convincing evidencethat this is true for the most important measureof therapeutic responsei.e., survival. Parasiteclearanceis widely usedas a measureof the therapeutic responsein malariabut it is worth asking: why should rapid removal of ring-form infected erythrocytes from the circulation save life? It is the mature parasitesin cytoadherent erythrocytes sequesteredin the microvasculatureof vital organsthat are thought to causepathology in malaria.Thus it is the parasiteswe cannotsee,not the oneswe cansee,i.e. it is the current asexualcycle, not the next, which may kill the patient (White & Krishna, 1989:Transactions, 83, 767-777). Obviously, the dynamicsand stage-specificityof antimalarial action, as well as the pharmacokineticpropertiesof the drug, are critical determinants of therapeutic outcomebut as yet we do not know the relative importance of these factors, nor have they been adequately characterized. Professor Salako and his colleaguesrightly recommendfurther carefully monitored studiesbefore advocatingroutine useof intramuscularS-P in cerebralmalaria(a recommendation
557
that seemshard to reconcile with their earlier statements).A great deal more evidenceis certainly required, and eventually this must be obtainedfrom severely ill children, not oligosymptomaticimmune adults. Finally, on a separatepoint, we recommended intramuscularchloroquineregimensof 3.5 mg base/ kg six-hourly or 2.5 mg base/kgfour-hourly in severe chloroquinesensitivemalaria(White et al., 1988:New England
3ournal
of Medicine,
319, 1493-1500),
rwt
3.5 mgibasekgkghr-hourly asstatedin the introduction of ProfessorSalako’spaper. Nicholas J. White Wellcome-Mahidol Universihhoxford Tropical Medicine Research-Probamme Facultv of Troika1 Medicine Mahi& bziv&ity 42016 Rajvithi Road Batl$&ok& 10400 22 November 1990
Sulfadoxine-pyrimethamine for the treatment of malaria: a reply In reply to Dr N. J. White’s letter [above], I should like to point out that intramuscular sulfadoxinepyrimethamineis widely availablebut is very rarely used.We gavethe reasonfor this stateof affairsin our paper and thought a re-evaluationwas called for (a similar re-evalu&ion by us of chloroquine in a series of papersfrom 1979helned in oreventine that verv useful drug from being prematurely dumped in Africa). We felt that re-evaluation should start, on ethical grounds,in patientsnot in immediatedanger of their life-adult Africans. If it turns out not to be effective and acceptablein that group, there would clearly be no justification for testing it in children whoseillnesscan progressrapidly wi& inappropriate therapy. If it were found to be usefulin adults then a trial in children could be justified. This is precisely what we have done. Following our demonstrationof satisfactory effect in adults, we conducted another trial in children, the results of which will soon be published. We now think there is iustification for cautiousevaluationin severeand complicatedmalaria, which we are soon to embark upon. Department of Pharmacology College of Medicine University of Zbadan Zbadan Nigeria
Fntagous
Lateef A. Salako and Therapeutics
beenobservedalsoin casesof visceralleishmaniasis. As indicated by ProfessorsRioux and Lanotte, the strains producing the cutaneous forms are more commonly enzymatic variants of MON-1, and the zymodeme variants isolated from skin lesions are seldomor never presentin visceral isolates.Finally, thev indicated that the so-calledL. chagasi. from visceralcasesin 6 Latin American count&, including Honduras,alsocorrespondedto their zymodeme MON-1. The questionthen arises,whether the presenceof cutaneousleishmaniasisdue to L. infantum, in a certain geographicalarea,dependson the strainof the parasiteinvolved, or on other factors associated with the human host, or both. We pointed out, as a characteristicof our focus, that no visceral clinical casehas ever been observedin CostaRica. On the other hand, a recent report (Ponce et al., 1991: Lancer, 337, 67-70) described17 atypical cutaneous cases,produced bv L. donovani chaaasi. identical to thosefrom CostaRica; theseoccur&d in an areaof visceralleishmaniasis in Honduras.lessthan 400 km from our focus. Assuming that the parasite is the same,how can we explain this important difference between the 2 foci? We know that Costa Rica has better sanitary conditions,with a lower child mortality rate and a lower malnutrition index, than Honduras. A prospective study made by ProfessorR. Badar6and his group in Bahia, Brazil (Badar6et al., 1986: Journal of Infectious Diseases, 154, 639-649; Cerfet al., 1987:bid., 156, 1030-1033)suggested that malnutrition and concomitantinfectious diseases, at an early age, are 2 important risk factors in the acquisition of the classicalpicture of visceral leishmaniasis.In the absenceof theserisk factors, a good immunologicalresponsemay determine that asymptomatic casesevolve to spontaneouscure (Badar6et al., 1986: 3ownal of Infectious Diseases, 154, 10031011). Perhapsthis favourableresponsemay alsolimit the diseaseexclusively to a cutaneousform, asin the CostaRica casesand in someHonduran ones. Since the Central American cutaneous picture is not observedin Brazil, we believe that particular strain characteristicscould also be involved in the final clinical picture and its resolution. In relation to the decline of visceral leishmaniasis during recent years in Italy, Bettini et al. (1983: Annales
27 December 1990
leishmaniasis and Leishmania
in-
ProfessorsRioux and Lanotte (1990: Transactions, 84, 898)referred to our Short Report (1989: Transactions, 83? 786) on a focus of atypical cutaneous leishmamasisproduced by Leishmania infanturn in north-westCostaRica. After our report appeared,the group from Montpellier sentme a seriesof paperson their valuable contributions regarding the various asnectsof a cutaneoustvne of leishmaniasis due to L. infanturn occurring in- several countries of the Mediterranean basin. Thev reoorted (Rioux et al.. 1986:Transactions, 80, looklob5) that,‘ in France, at least 5 different zymodemesof the parasite could produce this picture and one of them (MON-1) had
de Parasitologic
Hum&u
et Comparie,
58,
539-547)statedthat improvementof nutrition in the post-warperiod ‘might be one of the factors inherent to the decreaseof overt visceralleishmaniasis cases...’ Whether or not the Honduran and Costa Rican strainsof the parasiteareidentical, and factorsrelated to the human host and to the local conditions are responsiblefor the absenceof the classicalvisceral picture in the latter, remainsto be demonstrated. PZET Escuela de Medicina Universidad National Heredia, Costa Rica
Rodrigo
Zeled6n
Veterkria 1 April 1991
Mebendazole in giardial infections: co&ation of the failure of this treatment We havereadwith interestthe controversybetween Dr Noori S. Al-Waili and Drs J. Gasconand M.