Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant...

Acta Tropica 77 (2000) 185–193

Interaction between chloroquine and diversepharmacological agents in chloroquine resistant Plasmodium

yoelii nigeriensis

Naresh Singh, S.K. Puri *Di6ision of Microbiology, Central Drug Research Institute, Lucknow 226001, India

Received 11 September 1998; received in revised form 1 May 2000; accepted 22 June 2000

Abstract

The effect of a number of pharmacological agents on the enhancement of antimalarial activity of chloroquine wasevaluated against chloroquine resistant line of Plasmodium yoelii nigeriensis (N-67). The response after combinationtherapy was monitored on the basis of alteration in the course of parasitaemia, the extension of mean survival timeand the percent cure rate in different groups. The study was designed to compare the in vivo efficacy of a numberof resistance modulating agents found effective in several in vitro studies against chloroquine resistant P. falciparumisolates. Based on their efficacy in this rodent model, the response of combination of chloroquine with agentsrepresenting diverse chemical moieties has been categorised as curative, moderately active and inactive. Out of the 22agents evaluated, only cyproheptadine-chloroquine combination produced curative response. Ketotifen, azatadine,pheniramine, amitriptyline, fluoxetine, verapamil, penfluridol and trifluoperazine demonstrated moderate activitywhile loratadine, terfenadine, promethazine, ranitidine, nifedipine, diltiazem, chlorpromazine, amiodarone, tamoxifen,dipyridamol, propranolol, acyclovir and amantidine were inactive. The study advocates the suitability of proposedrodent model to shortlist potential resistance reversal agents. © 2000 Elsevier Science B.V. All rights reserved.

Keywords: Plasmodium yoelii nigeriensis ; Chloroquine resistance reversal; Cyproheptadine; Ketotifen; Azatadine; Pheniramine;Amitriptyline; Fluoxetine; Verapamil; Penfluridol; Trifluoperazine

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1. Introduction

Malaria remains the major cause of mortalityand morbidity and is considered most seriousimpediment to the socio-economic progress inmost of the tropical and subtropical regions. The

increasing prevalence of drug resistant Plasmod-ium falciparum although has hindered the abilityto control/treat the disease but at the same timehas intensified attempts to develop novel anti-malarial drugs and agents to prolong the clinicalutility of the few currently available drugs.Chloroquine had been the mainstay of antimalar-ial chemotherapy since its introduction over 50years ago because of high efficacy against suscep-

* Corresponding author. Fax: +91-522-223405.E-mail address: [email protected] (S.K. Puri).

0001-706X/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.

PII: S 0001 -706X(00 )00133 -9

N. Singh, S.K. Puri / Acta Tropica 77 (2000) 185–193186

tible parasites, ready availability, low cost and fewadverse effects. The efforts to extend clinical lifeof chloroquine especially has become importantfor several reasons. Alternate strategies directedto retain the clinical utility of chloroquine forcontrol of malaria need to be developed andevaluated. One approach that had shown promis-ing results in several in vitro studies has been theexploration of drugs capable of modulatingchloroquine resistance in combination.

Several in vitro studies have documented com-pounds of diverse chemical classes capable ofcausing reversal of resistance to chloroquine whenused in combination with the latter (Martin et al.,1987; Bitonti et al., 1988; Peters et al., 1989;Basco et al., 1991; Gerena et al., 1992; Ndifor etal., 1993; Evans and Havlik 1993; Basco and LeBras 1994). However, the application of this phe-nomenon in human infections has not yielded thedesired results. A perusal of limited in vivo studiescarried out with these agents in rodent modelsreveal that a uniform interpretation of results isnot possible because of use of different parasitemodels, treatment regimens or protocols. Potenti-ation of chloroquine by calcium antagonists hasbeen documented by Tanabe et al. (1990) againstP. chabaudi and Valecha et al. (1992) against P.berghei. Deloron et al. (1991) by using enan-tiomers of amlodipine against P. yoelii modelshowed such potentiations to be independent ofcalcium channel blocking properties. Miki et al.(1992) reported enhancement of chloroquine effi-cacy by tricyclic antidepressants againstchloroquine resistant P. chabaudi and Peters et al.(1990) recorded resistance modulation by severalantihistaminic agents against P. yoelii parasites.Though all these reports demonstrated enhance-ment of the activity of chloroquine, a total cura-tive response was not monitored in any of theabove studies. This report, presents results of acomparative assessment of potentiating efficacy ofdiverse agents in combination with a fixedchloroquine dose against a highly chloroquineresistant P. yoelii strain. The response of combi-nation chemotherapy was monitored up to 28days to allow monitoring of curative effect as wellas a comparison of degree of parasitaemia indifferent treatment groups.

2. Materials and methods

2.1. Host

Random bred Swiss mice (2092 g) of eithersex were procured from Institute’s animal facili-ties and housed under standard laboratory condi-tions. The animals were maintained oncommercial pellet diet and water ad libitum.

2.2. Parasite

The strain of P. yoelii nigeriensis (N-67), origi-nally obtained from Malaria Research Centre,Delhi, India in 1992 has been used for the presentstudy. This strain shows moderate level of innateresistance to chloroquine, as has also been docu-mented by Warhurst and Killick-Kendrick (1967),and has been designated as Py-R1 for the presentstudy. Another isolate designated Py-R2 which isresistant to maximum tolerated doses ofchloroquine was selected after exposing the parentisolate to increasing chloroquine pressure for fivesuccessive serial passages.

2.3. Test agents

Commercial samples of the following agentshave been used for the study: Cyproheptadine(Alvaetra lab Ltd., India), Ketotifen (Sun PharmaLtd., India), Azatadine (Fulford Ltd., India), Lo-ratadine (Cadila Health Care Ltd., India), Terfe-nadine (Cipla Ltd., India), Pheniramine (HoechstLtd., India), Promethazine (Rhone-Poulenc Ltd.,India), Ranitidine (Glaxo Ltd., India),Amitriptyline (Emil Pharma Ltd., India), Fluox-etine (Cadila Pharma Ltd., India), Verapamil(Boehringer Mannheim Ltd., India), Nifedipine(E Merck Ltd., India), Diltiazem (TorrentPharma Ltd., India), Penfluridol (TorrentPharma, Ltd. India), Trifluoperazine (Pharma-pack Ltd., India), Chlorpromazine (Rhone-Poul-nec Ltd., India), Amiodarone (Torrent PharmaLtd., India), Tamoxifen (Torrent Pharma Ltd.,India), Dipyridamol (German Remedies Ltd., In-dia), Propranolol (Cipla Ltd., India), Acyclovir

N. Singh, S.K. Puri / Acta Tropica 77 (2000) 185–193 187

(Burroughs Wellcome Ltd., India) and Aman-tidine (Cipla Ltd., India).

2.4. Experimental procedure

Animal of either sex were inoculated intraperi-toneally with 1×106 parasitized erythrocytes ofeither of the two isolates and distributed ran-domly to different experimental groups. The testagents were suspended in water and administeredorally for four consecutive days (day 0 to +3)either alone or in combination with chloroquine.The freshly prepared solutions of resistance mod-ulating agents at desired concentration were ad-ministered in two divided daily doses (09:00 and17:00 h) while chloroquine was administered oncedaily (09:00 h). Giemsa stained thin blood smearswere microscopically examined from day 4 on-wards up to day 28 to monitor the level ofparasitaemia. The animals which did not developpatent infection up to day 28 were recorded ascured. The resistance modulating potential of dif-ferent agents was compared on the basis of levelof parasitaemia in combination versus individualcomponent treated mice, extension of mean sur-vival time and the percent cure rate achieved indifferent groups.

3. Results

3.1. Chloroquine sensiti6ity of the parent andresistant isolates of P. yoelii nigeriensis (N-67)

P. yoelii nigeriensis is known to possess moder-ate level of resistance to chloroquine since itsisolation. By exposing the parent isolate to gradu-ally increasing chloroquine dosages for five suc-cessive serial passages an isolate showing highlevel of resistance to chloroquine was obtained.The chloroquine sensitivity pattern of the parentstrain (Py-R1) and the derived resistant strain(Py-R2) has been compared in Table 1. The re-sults indicate delayed patency after treatment withchloroquine at 16 mg/kg or higher doses in miceinoculated with Py-R1 strain. However the pat-tern of infection in mice inoculated with Py-R2isolate was similar in chloroquine treated andvehicle treated groups.

3.2. Antimalarial response of test agents againstP. yoelii nigeriensis (Py-R1) isolate

The antimalarial profile of twenty two diverseagents was initially evaluated against the parentP. yoelii nigeriensis (Py-R1) strain to determine

Table 1Course of infection with P. yoelii nigeriensis parent (Py-R1) and chloroquine resistant (Py-R2) isolates after chloroquine treatment

Mean survival time9S.E.Mice alive onMean percent parasitaemia (9SE) on dayDosea (mg/kg)(days)bday 28

4 7 10 16 28

Parent strain (Py-R1)Nil 3.290.4 9.891.18 47.295.3 Nil 5/12 16.990.9

16 NilNil 7/12 18.490.9Nil 3.290.7 27.493.4Nil 8.891.3 Nil 10/12 21.090.7Nil32 NilNil 5.891.4 Nil 11/12 21.090.064 NilNilNilNil 28.090.0c12/12Nil Nil128 5.790.8

Chloroquine resistant strain (Py-R2)2.790.3 44.494.9 Nil 4/12 15.191.411.891.116 31.893.71.890.2 10.191.2 22.392.032 45.094.0 Nil 4/12 16.891.3

64 18.291.85.990.8 15.691.07/12Nil1.690.2 43.792.91.390.2128 10.891.5 17.993.3 Nil 10/12 17.591.14.890.8

a Chloroquine dose, administered orally, once daily×4 days (0–3).b MST determined for those animals which died within day 28.c Observation ended with day 28.


their inherent antimalarial activity, if any. Theresponse was evaluated after four dose treatment(day 0–3) with cyproheptadine, ketotifen,azatadine, loratadine and trifluoperazine at 10mg/kg/day and terfenadine, pheniramine,promethazine, ranitidine, amitriptyline, fluoxetine,verapamil, nifedipine, diltiazem, penfluridol,chlorpromazine, amiodarone, tamoxifen, dipyri-damol, propranolol, acyclovir and amantidine at50 mg/kg/day regimens. The mean day-4 para-sitaemia for 12 mice in control group was 15.290.7% and all the mice died with a mean survivaltime of 7.090.8 days. Inherent antimalarial activ-ity was observed in cyproheptadine treated groupas all the mice were aparasitaemic on day-4. Thepatent infection developed subsequently in allthese animals and four of the six mice died show-ing a mean survival time of 14.891.5 days. Like-wise suppressive activity was also observed inketotifen treated group as indicated by lower day-4 parasitaemia (0.790.2%) and four of the sixmice survived and became aparasitaemic by day28. Treatment with rest of the agents did notproduce marked effect on the level of para-sitaemia. However, the mean survival time aftertreatment with azatadine, loratadine, terfenadine,pheniramine, amitriptyline, fluoxetine, diltiazem,penfluridol, trifluoperazine, chlorpromazine, acy-clovir and amantidine was extended by 1.5 timesthe value for control group.

3.3. Concurrent administration of di6erse agentswith chloroquine against P. yoelii nigeriensis(Py-R2) isolate

In order to determine their resistance modulat-ing potential, the diverse pharmacological agentsused above were administered in combinationwith 16 mg/kg chloroquine to groups of 12 miceeach infected with chloroquine resistant (Py-R2)parasites. The therapeutic response of combina-tion treated and chloroquine treated groups wascompared on the basis of degree of infection andthe mean survival time. The 24 untreated controlgroup mice died between days 6 and 10 (mean7.890.9 days) after attaining parasitaemia levelsexceeding 50%. Another 24 mice treated with 16mg/kg chloroquine alone developed patent infec-

tion on day-4 and the peak parasitaemia wasreached between days 13 and 16. Nearly 67%(16/24) mice succumbed to infection with a meansurvival time of 14.591.6 days. Eight of 24 micewhich survived after chloroquine monotherapywere able to clear the infection and became micro-scopically aparasitaemic by day 28. Concurrentadministration of chloroquine with cyprohep-tadine at 10 mg/kg showed curative response asnone of the 12 mice developed infection during 28days observation period. The combination withketotifen, azatadine and pheniramine also showedsignificant activity as assessd by either the delayedpatency or the decreased parasitaemia level in thetreated mice. Patent infection developed in all themice treated with the above three combinations,however, the level of parasitaemia in combinationtreated groups was significantly lower thanchloroquine alone treated group. Moreover 10/12,10/12 and 8/12 mice, respectively, in the threegroups cleared the parasitaemia by day 28. Asimilar response was observed after concurrentadministration of chloroquine with antidepressantagents amitriptyline, fluoxetine and verapamil aswell as neuroleptic agents penfluridol and trifluop-erazine, where the degree of parasitaemia betweendays 4 and 13 was markedly lower compared tochloroquine alone. Moreover 8, 8, 8, 11 and 8mice, respectively, in these combination groupscleared the infection. The course of infection incombination groups comprising other agentsnamely loratadine, terfenadine, promethazine,ranitidine, nifedipine, diltiazem, chlorpromazine,amiodarone, tamoxifen, dipyridamol, propra-nolol, acyclovir and amantidine was not signifi-cantly different to that of chloroquine alonetreated group. However, except for three combi-nation groups comprising promethazine, rani-tidine and diltiazem, a proportionately largernumber of mice varying between six and tencleared the infection after treatment with theother agents. A comparison of the mean survivaltime of the animals which died in different treat-ment groups showed marked prolongation in 4/12mice after treatment with chloroquine-verapamilcombination.


3.4. Concurrent administration of chloroquine andcyproheptadine against P. yoelii nigeriensis(Py-R1 and Py-R2) isolates

In view of curative response observed withchloroquine and cyproheptadine combinationagainst resistant parasites, further experimentswith different dose combinations of two agentswere carried out as detailed in Tables 2 and 3.Against Py-R2 isolate, combination ofchloroquine 16 mg/kg with cyproheptadine 10mg/kg was curative in all the 12 mice (Table 2).Similar response was observed in 6/12 micetreated with chloroquine 8 or 16 mg/kg pluscyproheptadine 10 mg/kg combination while sig-nificant suppression of parasitaemia was recordedin the remaining 6 mice which developed patentinfection. Marked suppression of parasitaemiawas also observed during the first 10 days inanimals with chloroquine at 8 mg/kg in combina-tion with 5 mg/kg cyproheptadine in comparisonto animals treated with either of the two compo-nents alone. Combination studies withchloroquine and cyproheptadine against parent(Py-R1) strain were also taken up to observe thepattern of response. Results in Table 3 show thatcombination of cyproheptadine 10 mg/kg with 4,8 or 16 mg/kg protected all the treated mice indifferent groups. However, patent infection devel-oped in all the mice when lower dose of cyprohep-tadine (5 mg/kg) was used in combination with 8or 16 mg/kg chloroquine.

4. Discussion

Amongst the different categories of agents eval-uated, moderate to high degree of enhancement ofthe activity of chloroquine could be observed withfour antihistaminic, two antidepressant, two neu-roleptics and one calcium channel blocking agent.The interpretation of the response to treatmentwith the drug combinations was monitored on thebasis of effect on sequential development of para-sitaemia vis-a-vis the pattern recorded withchloroquine alone. The capacity to prevent devel-opment of patent infection marked the maximumactivity while significant suppression of para-

sitaemia level during the early phase of infectionwas categorised as the moderate response. Com-parison between chloroquine alone and combina-tion treated groups on the basis of increased meansurvival time did not yield any worthwhile indica-tions. However, data on percent survival and thecapacity to clear the infection to subpatent levelsupplements the results with effect on course ofparasitaemia and can serve as an complimentaryparameter to select potentially useful agents.

Cyproheptadine was the most potent of thefour antihistaminic agents, since none of the micedeveloped infection when 10 mg/kg dose of cypro-heptadine was used. Dose response studies withlower doses of chloroquine or cyproheptadineshowed moderate activity against resistant para-sites. However, against the parent strain, combi-nation of 4 mg/kg chloroquine with 10 mg/kgcyproheptadine was curative, while 16 mg/kgchloroquine with 5 mg/kg cyproheptadine pro-duced only marginal response. The results thussuggest that a relatively higher dose of cyprohep-tadine is essential to obtain the curative response.Of the other antihistaminic agents, ketotifen,azatadine and pheniramine produced moderateeffect in combination with chloroquine. Similarresponse was also recorded with amitriptyline,fluoxetine, verapamil, penfluridol and trifluop-erzine. However, none of these agents providedcomplete protection in any of the treated mice.Cyproheptadine and ketotifen also exhibited lowlevel of antimalarial activity when used aloneagainst P. yoelii parasites. The results obtained inthis study with combination of cyproheptadineand chloroquine are in contrast with those ob-served in a clinical study with P. falciparum in-fected patients (Bjorkman et al., 1990) wherein adose of 0.3 mg/kg twice daily ×5 days in combi-nation with chloroquine failed to enhance thedrug response. In the same study, in vitro testsshowed potentiation of the activity of chloroquinewith 1 nM concentration of cyproheptadine infour P. falciparum isolates. The author observedthat the failure of activity enhancement in vivocould be attributed to insufficient peak plasmaconcentration (0.3–0.5 nM) attained with thedose used in the study. In another study, identicalobservations were made by (Warsame et al., 1992)


Tab

le2

Cou

rse

ofin

fect

ion

wit

hP

.yo

elii

nige

rien

sis

Py-

R2

stra

inaf

ter

trea

tmen

tei

ther

alon

eor

inco

mbi

nati

onw

ith

cypr

ohep

tadi

nean

dch

loro

quin

e

Mic

eal

ive

Mea

nsu

rviv

alD

rug

(s)

(mg/

kg)

Mea

npe

rcen

tpa

rasi

taem

ia(9

S.E

.)on

day

No.

cure

d/ti

me9

S.E

.(d

ays)

bon

day

28no

.tr

eate

dC

hl.+

Cyp

.a

2816

107

4

Nil

0/12

415

.89

1.2

47.59

2.8

17.09

3.2

410

3.59

0.6

8.39

1.4

Nil

6/12

1228

.09

0.0c

810

Nil

Nil

0.39

0.2

4.99

1.7

Nil

12/1

212

28.09

0.0c

Nil

16N

ilN

ilN

il10

8N

il5

0/12

820

.59

1.1

Nil

Nil

1.79

0.6

16.29

2.9

Nil

0/12

623

.09

0.8

5.59

0.9

16N

ilN

ilN

il5

0/12

013

.59

1.5

4–

7.29

0.7

18.39

3.0

44.39

4.3

67.59

1.8

0/12

016

.29

1.0

66.09

2.6

833

.99

3.0

18.29

3.0

6.89

0.6

–N

il16

0/12

–5

17.19

1.1

6.19

0.7

12.79

1.5

31.39

2.8

49.19

6.3

Nil

0/12

416

.59

1.2

23.89

3.3

17.09

2.4

–10

Nil

2.09

0.2

0/12

Veh

icle

cont

rol

013

.89

1.5

7.79

0.6

50.39

6.4

78.09

0.0

aC

hl.,

chlo

roqu

ine;

Cyp

.,cy

proh

epta

dine

.b

MST

dete

rmin

edfo

rth

ose

anim

als

whi

chdi

edw

ithi

nda

y28

.c

Obs

erva

tion

ende

dw

ith

day

28.


Tab

le3

Cou

rse

ofin

fect

ion

wit

hP

.yo

elii

nige

rien

sis

Py-

R1

stra

inaf

ter

trea

tmen

tei

ther

alon

eor

inco

mbi

nati

onw

ith

cypr

ohep

tadi

nean

dch

loro

quin

e

Mic

eal

ive

No.

cure

d/M

ean

perc

ent

para

sita

emia

(9SE

)on

day

Mea

nsu

rviv

alD

rug

(s)

(mg/

kg)

no.

trea

ted

tim

e9S.

E.

(day

s)b

onda

y28

Chl

.+C

yp.a

284

710

16

Nil

12/1

212

28.09

0.0c

Nil

Nil

Nil

410

Nil

Nil

12/1

212

28.09

0.0c

810

Nil

Nil

Nil

Nil

Nil

12/1

212

28.09

0.0c

Nil

16N

ilN

ilN

il10

8N

il5

0/12

619

.09

0.5

Nil

Nil

3.39

0.9

26.79

4.0

Nil

0/12

1228

.09

0.0c

18.79

3.1

161.

09

0.5

Nil

Nil

5N

il0/

124

16.39

1.2

4–

0.59

0.2

3.39

0.6

13.59

2.2

41.39

6.2

Nil

0/12

618

.09

1.3

41.09

6.5

83.

39

0.7

1.59

0.2

Nil

–N

il16

0/12

–12

28.09

0.0c

Nil

Nil

2.79

0.7

8.59

1.6

Nil

0/12

415

.09

1.1

30.09

6.4

8.29

1.2

–10

Nil

1.39

0.5

0/12

Veh

icle

cont

rol

017

.69

1.2

7.39

0.6

62.59

4.0

aC

hl.,

chlo

roqu

ine;

Cyp

.,cy

proh

epta

dine

.b

MST

dete

rmin

edfo

rth

ose

anim

als

whi

chdi

edw

ithi

nda

y28

.c

Obs

erva

tion

ende

dw

ith

day

28.


where chloroquine in combination with de-sipramine (1.3–2.8 mg/kg ×3 days) was not ef-fective in altering the response to chloroquine inpatients harbouring chloroquine resistant falci-parum malaria infection. The desipramine doseused in this report was expected to provide amean plasma concentration of 0.15×10-6 mol/lwhich is far below the 0.625×10-6 mol/l concen-tration producing total reversal of resistance inwild isolates of P. falciparum in vitro. De-sipramine showed moderate activity in the presentstudy. Kyle et al. (1993) have also reported thelack of potentiation of chloroquine efficacy withcyproheptadine and ketotifen against P. falci-parum in Aotus monkey model even though afairly high dose of 20 mg/kg (once daily ×7 days)was used. The authors indicated differences in thepharmacokinetics of drug combination in miceand monkeys or the differences in mechanism ofchloroquine resistance in rodent and humanmalaria as the possible factors responsible for thecontrasting results. Cyproheptadine is therapeuti-cally used at 5 mg/kg dose administered two tothree times a day and it is doubtful whetherexploration of higher doses is justified as theyapproach a potential toxic range. More informa-tion on optimum dose regimen, pharmacokineticsof drug combination of such agents in combina-tion with chloroquine is contemplated for clinicaluse. However, the encouraging results with someof these agents suggest that useful resistance mod-ulators may be eventually available to protectconventional antimalarials.

The negative results obtained in the study withloratadine, terfenadine, promethazine, ranitidine,nifedipine, diltiazem, chlorpromazine, tamoxifen,dipyridamol, propranolol, acyclovir and aman-tidine indicate suitability of this model system toidentify and shortlist potential resistance modulat-ing agents. This study, to our knowledge is thefirst report in a rodent model system where re-sponse following drug treatment with severalmodulating agents has been monitored for longerduration. This enables to categorise the testagents, on the basis of their activity, in threedistinct subsets as curative, moderately effectiveand inactive. The rodent model system presentedhere would be useful for assessing new agents for

in vivo reversal of chloroquine resistance to de-velop a clinically useful resistance modulator.

Acknowledgements

The authors are grateful to Drs C.M. Gupta,Director and B.S. Srivastava, Head of the Divi-sion of Microbiology, Central Drug Research In-stitute, Lucknow, India for constantencouragement and support. The authors are alsothankful to G.P. Dixit, K.K. Singh and Sant Ramfor technical assistance. Financial assistance in theform of fellowship under CDRI-WRAIR Collab-orative Project DAMD 17-93-J-3019 to one of theauthors (NS) is acknowledged. This report is com-munication no. 5869 from CDRI.

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Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant...

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