A comparative study of medications being  used for malaria treatment in Zimbabwe

Chandiwana, S.

Mharakurwa, S.

Mutetwa, S.

Neill, P.

Simooya, O.

Stein, M.

Central African Journal of Medicine

English

IDS OpenDocs

The
Central African 
Journal 
of
Medicine
Supplementary Issue to 1992 Volume 38,
1991 University of Zimbabwe Annual Research Day
THE CENTRAL AFRICAN
JOURNAL OF MEDICINE
Vol. 38, No. 7, July 1992
THE CENTRAL AFRICAN 
JOURNAL OF MEDICINE
ORIGINAL ARTICLES
A comparative study of 
the Schizontocidal efficacy 
and safety of artemether 
versus chloroquine in 
uncomplicated malaria
O S IM O O Y A S  MUTETWA1 
S CHANDIWANA,2 P NEILL1 
S MHARAKURWA,2 M STEIN1
SUMMARY
Forty-seven patients with uncomplicated falciparum 
malaria were randomly assigned to receive either 
artemether (n=24), 9,6 mg/kg body weight intra­
muscularly over five days or chloroquine (n=23), 25 
mg/kg body weight orally. Patients were kept in 
hospital for seven days followed by review on days 
14, 21 and 28. Five patients on chloroquine were 
withdrawn before day seven due to treatment failure.
Of the remaining patients, parasite clearance time 
was 33.0 ± 13.6 hours for the artemether group and
63.3 ± 14.7 hours for patients on chloroquine 
(p<0,001). No significant difference was recorded in 
fever clearance time between the two groups of 
patients.
Recrudescence rate for patients on artemether was
14.3 pc compared to 57,1 pc for the chloroquine
[Medical School, Box AJ78, Harare, Zimbabwe 
Blair Research Laboratories, Box 8105, Harare, 'Zimbabwe 
* Author fo r correspondence
group (p<0,05). No major adverse events were 
recorded for either treatment group although five 
patients on artemether had a transient spike of 
temperature after clearance of parasitacmia.
In conclusion, our study has shown that no major 
adverse events were experienced by patients on 
artemether and the rate of parasite clearance for the 
artemether group was superior to that of patients on 
chloroquine.
INTRODUCTION
Artemether is a lipid soluble derivative of Qinghaosu 
(Artemisinin), an anti malarial compound isolated 
from the Chinese herb Qinghao (Artemisia annual L.) 
Although a number of reports have been documented 
regarding the safety and efficacy of artemether in the 
treatment of falciparum malaria, many of these 
studies have been uncontrolled and were conducted 
in China where the parent drug has been in use for 
over a thousand years.1
Given the rapidly spreading problem of resistance 
to standard antimalarials by falciparum malaria 
world wide, the need to assess artemether and other 
derivatives of artemisinin in different parts of the 
world has assumed an urgent importance.
MATERIALS AND METHODS
(a) Study Location: The study was conducted at the
Gokwc District Hospital in Gokwe. Gokwc District
is situated in the Midlands Province of Zimbabwe
and records one of the highest incidences of malaria 
2
in Zimbabwe.
(b) Patient Selection: Between the months of 
April to July 1991, all patients presenting to hospital
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THE CENTK AL AFRICAN
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Vol. 38, No. 7, July 1992
with a positive blood smear for P. falciparum and a 
temperature of greater than 38°C were eligible to 
participate.
Patients with the following conditions were 
excluded: those below the age of 14 years and those 
aged above 60; pregnant or breast feeding women; 
evidence of im pairm ent o f renal, hepatic or 
cardio-vascular systems; a history of antimalarial 
ingestion two weeks before presentation and/or a 
positive Dill Glasko urine test for 4-aminoquinolines; 
those unwilling to give informed written consent.
All patients satisfying the entry criteria were 
admitted to the medical wards of the hospital for an 
initial seven day observation period followed by an 
outpatients review on days 14, 21 and 28.
The possibility of reinfection was minimised by 
giving each patient an insect rcpcllant to use all over 
the body on discharge.
(c) Drug Administration: The study was an open 
comparative trial and patients w'erc randomly 
assigned to receive cither artemether or chloroquine.
Artemethcr was obtained from the Kunning 
Pharmaceutical Company of Yunan, China and w'as 
given at an initial dose of 160mg intramuscularly 
(IM), followed by 80mg IM daily over the next four 
days, a total dose equivalent to 9,6mg/kg body weight 
(BW).
Chloroquine phosphate (Norolon) was given 
orally at an initial dose of lOmg/kg BW followed by 
5mg/kg BW after six hours and then 5mg/kg BW 
daily for tw'o days, a total dose equivalent to 25mg/kg 
BW.
Paracetamol was the only analgesic allowed 
during the trial and those patients whose parasitacmia 
did not respond to the trial drugs were treated with 
either sulfadoxine/pyrimethaminc (FANSIDAR) or 
quinine.
(d) Assessment C riteria: (i) Sensitivity to 
chloroquine: Sensitivity of P. fa lc ip a ru m  to 
chloroquine was determined by an in vitro micro test 
before treatment.3
(ii) Parasitological response: Parasite count per 
microlitre of blood was determined before treatment
by counting the number of parasites per 200 White 
Blood Cells (WBC) and then multiplying the figure 
obtained by 30 (assuming a normal WBC of 6 000/ul 
in the population). Blood smears were then taken and 
examined 12 hourly until day seven. The time taken 
from the first dose of the drug to the first negative 
sm ear was counted as the “ time to parasite 
clearance".
(iii) Body temperature was taken four hourly after 
commencement of a treatment until day seven. 
“Time to fever clearance" was defined as the time 
taken for the temperature to return to normal (37,4°C) 
for eight hours after the first dose of the drug.
(iv) Recrudescence: After discharge, blood slides 
w ere repeated  on day 14, 21 and 28. The 
recrudescence rate was then calculated.
(v) Adverse events: All patient were asked daily for 
any adverse reactions experienced. Routine 
laboratory and biochemical examination was done 
before treatment and on days one, four and 28.
(vi) Statistical analysis: Mean values and standard 
deviation of the time to fever clearance, and time to 
parasite clearance were calculated and comparisons 
made using param etric statis tica l methods. 
Recrudescence rates were determined for each group 
and then compared by non-parametric testing.
RESULTS
A total of 47 patients were enrolled in the study. 
Twenty-four patients received artemethcr whilst 23 
were treated with chlorquinc. There was no 
significant difference in age, sex, body weight and 
height between die two groups of patients (Table 1).
(a) Parasitology Response: (i) In vivo findings: 
The mean parasite count in the artemethcr group was 
9 950/ul and 8 337/ul for the chloroquine patients 
(p>0,05) (Table Il.i.i).
Five patients treated with chloroquine did not 
complete the initial seven days observation period; 
three, due to positive smear and pyrexia 72 hours after 
initiation of therapy and the other two due to a 
persistent parasitaemia. All four were successfully 
treated with either sulfadoxine/pyrimethaminc 
(FANSIDAR) or quinine.
258
THE CENTRAL AFRICAN
JOURNAL OF MEDICINE
VoL 38, No. 7, July 1992
Table I: Demographic Characteristics o f 47 Malaria Patients, Gokwe 1991.
I.i Age distribution
Age class (years) Artemether
Treatment
chloroquine Total
14-19 4 9 13
20-25 7 4 11
26-33 7 5 12
34+ 6 5 11
Total 24 23 47
Chi-Square D.F. Prob.
3,15 3 0,37
l.ii Distribution of patients according to sex
Gender artemether
Treatment
chloroquine Total
male 18 18 36
female 6 5 11
Total 24 23 AT
Chi-Square D.F Prob.
0,07 1 0,79
0,00 1 1.00 after Yates correction.
!.iii Mean weight (kg)
artemether 58.3(8.6)* Cases=24
chloroquine 56.9(17.2) cases=23
t value D.F Prob.
0,36 45 0.72
*Standard deviation
l.iv Mean height
artemether 168,48(8.7)* cases=21
achloroquine 167.99(11.6) cases=20
t value D.F Prob.
0,16 39 0,87
*Standard deviation
Table I I :  Response to antimalarial treatment, Gokwe,1991
11.1 Parasitological response:
11.1.1 Initial mean parasitemia
artemether 9 950(6 061 )* cases=24
chloroquine 8 337(4 350) cases=23
t value D.F. Prob.
0,79 45 0,435 (calculated following log x +1 transformation).
*Standard deviation
259
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THE CENTRAL AFRICAN
JOURNAL OF MEDICINE
Vol. 38, No. 7, July 1992
tl.i.ii Mean tim e to parasite clearance ll.ii C linical response
Treatment
artemether
chloroquine
Time hours 
33,0(13,6) (24 cases) 
63,3(4,7) (18 cases)
ll.ii.i Mean time to fever clearance (hours)
treatment
artemether
chloroquine
22,8(10,3*)
22,9(8,4)
t value D.F. Prob. t value D.F. Prob.
6,87 3
‘ “ p<0,001
‘Standard deviation
4,7 0,000*** 0,03 3,43 
*Standard deviation
0,978
ll.i.iii In vivo sensitivity of parasites to day 28
Treatment Sensitive(S) S or Rl+ Treatment
failure
Rl(rateP) Lost before 
Day 7
artemether 16 3 0 3 (14,3 pc) 2
chloroquine 5 4 6 8 (57,1 pc) 0
LEVEL OF SIGNIFICANCE FOR RATE OF RECRUDESCENCE 
Chi-square D.F. Prob.
7.2 1 0,0075"
5.3 1 0,02* (after Yates correction)
**p<0,001
“ P<0,05
+represents patients sensitive up to seven but subsequently lost to follow up
"rate is based on 21 artemether patients seen after day seven and 14 chloroquine patients seen after day seven.
Figure I: Comparison o f artemether and chloroquine phosphate with respect to asexual parasite count through 
time.
TIME (hr*)
The figure compares mean asexual parasite counts as determined by thick smears taken at 12 hour intervals 
over seven days. Top line (chloroquine phosphate group),and bottom line (artemether group) showing mean 
parasite count and 95 pc confidence limits.
260
THE CENTRAL AFRICAN
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Vol. 38, No. 7, July 1992
ll.ii.ii Adverse events reported by patients
Event
Treatment
artemether chloroquine
pruritis 0
insomnia 4
diarrhoea 3
vomiting 0
dizziness 6
myalgia 3
headache 16
vertigo 1
tinnitus 1
body hotness 1
intlammation at site 1
of injection
abdominal pain 12
Total 48
''Indicates where expected frequencies were below the 
accepted limit for significance tests.
7A 
4 * 
0* 
3* 
6* 
1A 
14 
1A 
1A 
1A 
0A
8
46
Of the remaining patients the mean time to parasite 
clearance was 33,0 ± 13,6 hours for artemether (n = 
24) and 63,3 ± 14,4 hours for patients treated with 
chloroquine (n = 18) (p<0,001) (Table Il.i.ii and 
Figure I).
Two patients on artemether withdrew before day 
seven for personal reasons; both were slide negative 
at the time. Of the 22 artemether patients seen up to 
day seven, one never returned after discharge and two 
did not complete the 28-day observation period. 
Three of the 21 (14,3 pc) patients on artemether seen 
after day seven had a recrudescence of RI response 
and 16 were fully sensitive up to day 28, 
(Table Il.i.iii.)
Amongst the 18 chloroquine patients who were 
seen up to day seven, one recrudesced on day seven 
three were never seen again and one was lost to 
follow up after day 14. A total of eight out of 14 
(57,1 pc) chloroquine patients seen after day seven 
had a recrudescence or RI response and five were 
fully cured of their parasitaemia when seen on day 28 
(Table Il.i.iii.).
(ii) In vitro Findings: Seven in vitro micro tests 
were successful out of which four isolates were found 
to be resistant to chloroquine.
(b) Clinical Response: There was no difference in 
time to fever clearance between the two groups of 
patients (Table H.ii.i.).
No major adverse or toxic effects were recorded in 
cither group of patients. Seven patients treated with 
chloroquine experienced pruritis, an event not 
recorded in the artemether group. Only one patient 
had a mild inflammation at the site of injection in the 
artemether group and this subsequently resolved 
without treatment (Table ll.ii.ii.).
Five patients on artemether had a transient 
temperature spike after clearance of parasitaemia. 
Twelve patients on artemether complained of 
abdominal pains compared to eight on chloroquine. 
This finding however was not significant and 
resolved uneventfully.
DISCUSSION
Our study was the first one to use artemether for the 
treatment of falciparum malaria in Zimbabwe. To our 
knowledge, only two other studies of artemether have 
been reported in Africa.4,5 Overall, artemether was 
well tolerated and no major adverse events were 
recorded.
Five patients treated with artemether had a 
transient spike of temperature after clearance of 
parasitaemia. Transient pyrexia has been reported in 
previous artemether studies6 and although no 
explanation has been offered for it, we believe that 
this effect could be an idiosyncratic reaction to the 
drug itself as normal temperature is obtained within 
hours.
Parasite clearance was significantly faster with 
artemether than with chloroquine. Although the mode 
of administration of drug could affect the therapeutic 
outcome, it is a well-known fact that chloroquine is 
well absorbed orally and peak plasma concentrations 
of 250ug/litre have been obtained within two hours7
following a dose of lOmg/kg body weight.
On the other hand limited studies with artemether 
which is available as a suspension in peanut oil 
indicate that peak concentrations of 220ug/litrc arc 
attained six hours after a single intramuscular 
injection of lOmg/kg body weight. Our findings 
therefore compare well with those obtained by other 
workers.1’4,5,9 Eight of the 14 (57,1 pc) chloroquine
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THE CENTRAL AFRICAN
JOURNAL OF MEDICINE
Vol. 38, No. 7, July 1992
patients seen to day 28 had a recrudescence or RI 
response compared to only three (14,3 pc) of the 21 
artemether patients seen up to day 28 (p<0,001). In 
the absence of a mechanism to exclude entirely the 
possibility of reinfection, our figures may be higher 
than the actual situation prevailing in the district. 
However, when compared to previous studies, our 
recrudescence rate for artemether is much lower than 
the rate of up to 41,2 pc reported in China 10
S ix chloroquine patients did not complete the study 
due to treatment failure. This finding when taken 
together with the chloroquine recrudescence rate of
57,1 pc and the in vitro chloroquine resistance in four 
out of seven isolates, suggests that chloroquine 
resistant malaria is now established in the district.
No significant difference was found in mean time 
to fever clearance between the two groups of 
patients.This finding is similar to that found in 
Chinese and Nigerian studies where mean time to 
fever clearance for patients treated with artemether 
was less than 24 hours.1,4
Or study has therefore demonstrated that there was 
no major adverse event recorded in patients on 
artemether and more rapid clearance of parasitacmia 
was obtained with artemether when compared to that 
of chloroquine.
In Zimbabwe, quinine is the drug of choice for the 
treatment of severe or complicated malaria; we are 
therefore planning studies to compare artemether 
with quinine in this condition. The need for 
alternative drugs in the light of the ever increasing 
problem of drug resistant malaria cannot be over 
emphasised.
ACKNOWLEDGEMENTS
We arc most grateful to Mrs Jane Godwin, Clinical 
Research Associate of Pharmanova (Pvt) Ltd, and 
Sister G. Mandaza of Blair Research Laboratories 
(BRL) for providing excellent nursing care for the 
patients, Mr A Murahwa of BRL for his technical 
support and the Provincial Medical Director, 
Midlands Province for having given us permission to
carry out the study at the Gokwe District Hospital. 
Our appreciation also goes to the District Medical 
Officer,Gokwe, Dr Milton Chemhuru and hospital 
staff for their unwavering support. The artemether 
used in this study was sourced by Pharmanova (Pvt) 
Ltd. The statistical analysis was performed by Mr M 
Bradley of BRLand the manuscript was typed by Mrs 
R Madyambudzi of the Medical School. Lastly we 
are grateful to the Secretary of Health of the 
Government of the Republic of Zimbabwe, for his 
authority to publish the results of this study.
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2. Taylor P and Mutambu SL. A review of the 
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3. Rieckman KH, Champbcll GH, Sax U  and 
Mvcma JE. Drug sensitivity of Plasmodium 
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A comparative study of the schizontocidal efficacy and safety of artemether versus chloroquine in uncomplicated malaria

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A comparative study of the schizontocidal efficacy and safety of artemether versus chloroquine in uncomplicated malaria

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