See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/316630307

Quality of artemisinin-based antimalarial drugs marketed in Nigeria

Article  in  Transactions of the Royal Society of Tropical Medicine and Hygiene · April 2017
DOI: 10.1093/trstmh/trx019

CITATIONS READS

2 87

4 authors:

Oisaemi Izevbekhai Babatunde Ayodeji Adeagbo

University of Chemical Technology and Metallurgy Obafemi Awolowo University
4 PUBLICATIONS   11 CITATIONS    14 PUBLICATIONS   37 CITATIONS   

SEE PROFILE SEE PROFILE

Adeniyi Olagunju Oluseye Bolaji

Obafemi Awolowo University Obafemi Awolowo University
34 PUBLICATIONS   196 CITATIONS    66 PUBLICATIONS   484 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Viral and antiretroviral dynamics in HIV mother to child transmission View project

Optimization of the use of Imatinib Mesylate in Nigerians with Chronic Myeloid Leukaemia View project

All content following this page was uploaded by Oluseye Bolaji on 05 July 2019.

The user has requested enhancement of the downloaded file.

 Trans R Soc Trop Med Hyg 2017; 111: 90–96
doi:10.1093/trstmh/trx019 Advance Access publication 28 April 2017
ORIGINAL ARTICLE

Quality of artemisinin-based antimalarial drugs marketed in Nigeria

Oisaemi Izevbekhai*, Babatunde Adeagbo, Adeniyi Olagunju and Oluseye Bolaji

Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria

*Corresponding author: Present address: Department of Organic Synthesis and Fuels, University of Chemical Technology and Metallurgy,
Sofia, Bulgaria; E-mail: oisaze@yahoo.com

Received 24 January 2017; revised 17 March 2017; editorial decision 20 March 2017; accepted 3 April 2017

Background: Artemisinin combination therapy is first-line therapy for treatment of malaria, which is one of
the most significant public health problems in Nigeria. With the increasing level of use of these drugs coupled
with the emergence of resistance, there is a need for regular post-market surveillance.
Method: Twenty different brands of artesunate-containing antimalarial drugs and 10 brands of artemether–
lumefantrine were multi-sourced in the south western part of Nigeria and were subjected to identification,
weight uniformity test, and assay using United State pharmacopoeia and International Pharmacopoeia
monographs. In vitro-dissolution test of the artemether tablets was also investigated.
Results: All 10 brands (100%) of the artemether-lumefantrine tablets met the assay requirement for arte-
mether and 8 (80%) met the assay requirement for lumefantrine, but only 4 brands (40%) met the require-
ment for artemether dissolution. One of these brands failed the weight uniformity test. Of the 20 brands of
artesunate-containing brands included in this study, 15 (75%) met the standard assay requirement for artesu-
nate and two failed the weight uniformity test.
Conclusions: There is evidence of the presence of substandard artemisinin products in the Nigerian market.

Keywords: Artemisinin, Lumefantrine, Malaria, Nigeria

Introduction
Malaria remains one of the most challenging public health pro-
blems in Africa. In 2015, WHO estimated that there were 214
million new cases of malaria which resulted in 438 000 deaths,
with the majority of the cases (65%) being children under 15
years of age.1 Records show that in Nigeria, malaria accounts
for over 60% of all out-patient cases and that not less than
50% of the entire population suffers at least an episode of mal-
aria each year. The average incidence of malaria per 1000 of the
population is highest at 28 710 when compared with West
African regional average and the global average, which were
18 579 and 3752, respectively.1 Malaria also accounts for 11%
deaths in pregnant women, 25% of infant mortality and 30%
childhood mortality in the country. The resultant economic cost
may be as high as 1.3% of economic growth per annum.
In 2004, Nigeria modified its malaria treatment guidelines
and adopted artemisinin-based combination therapy, currently
considered as the best treatment for uncomplicated malaria, as
the first-line treatment of Plasmodium falciparum malaria.2 The
estimated 219 (154–289) million malaria cases reported glo-
bally in 2010 resulted in an estimated 0.66 (0.490–0.836) mil-
lion deaths. These represented 274 million fewer malaria cases
and 1.1 million fewer deaths compared to 2000 figures.3 This
achievement parallels similar progress in access to artemisinin-
based combination therapy (ACT) through the Affordable
Medicines Facility-malaria (AMFm) initiative of the Global Fund
through which 11 million ACT treatment courses were distributed
in 2005, increasing to 278 million in 2011.3 Sustaining these
achievements, and ultimately achieving the goal of malaria eradi-
cation, requires maintaining the effectiveness of current therapies.
However, several reports have confirmed the presence of
parasite resistance to the artemisinins in Cambodia, Myanmar,
Thailand and Viet Nam in the Greater Mekong sub-region where
earlier investigations revealed the presence of substandard
and/or counterfeit artemisinin derivatives before their adoption
as first-line therapy in Africa.4–7 For instance, Newton et al.
reported that 38% of shop-bought ‘artesunate’ samples from
Cambodia, Laos, Myanmar, Thailand and Viet Nam did not con-
tain artesunate (Figure 1).8 The limited number of drugs at late
development stage in the global antimalarial drugs pipeline9
makes the very thought of widespread ACT failure particularly
alarming. In fact, availability of substandard drugs has been
identified as one of the factors contributing to the emergence
of resistance.10 The overlap in the distribution of substandard

© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com.

90
Transactions of the Royal Society of Tropical Medicine and Hygiene
Figure 1. Proportions of fake artesunate samples in Greater Mekong
Asian sub-region.
artemisinins and the emergence of resistance to these drugs
emphasises the need for regular post-market surveillance of
antimalarial drugs qualities.
In the present study, we investigated the quality of ACT anti-
malarial drugs marketed in Nigeria.
Materials and methods
Chemicals and reagents
Potassium sulphate (monobasic) (Sigma-Aldrich, St. Louis, MO,
USA), trifluoroacetic acid (Hopkin and Williams, Chadwell Heath,
Essex, UK) 1-propanol, acetonitrile HPLC grade (Sigma-Aldrich),
1-hexane sulphonic acid sodium salt (Fischer Scientific, NH,
USA), artesunate reference sample, artemether reference stand-
ard, lumefantrine reference standard (all from Swiss Pharma,
Lagos, Nigeria), hydrochloric acid, benzalkonium chloride, ethyl
acetate, glacial acetic acid, acetone and hexane (also from
Sigma-Aldrich).
Instruments
Analytical balance (Mettler Toledo), UV spectrophotometer
(UNICAM UV1 and Cecil CE 3041), Agilent 1100 series liquid
chromatographic system (Agilent Technologies, Santa Clara, CA,
USA) fitted with a diode array detector. The column was a
Hypersil ODS (C18) 5 μm, 4.0×125 mm) reversed phase stainless
steel type (Agilent Technologies) and dissolution rate apparatus
(Veego Instruments Corporation, Mumbai, India).
Samples
Twenty different brands of artesunate-containing antimalarial
drugs and 10 brands of artemether–lumefantrine were multi-
sourced in the south western part of Nigeria. The identifying
features of each sample (commercial name, composition,
manufacturer, batch number, manufacturing date, expiry date,
marketer, and National Agency for Food Drug Administration
and Control [NAFDAC] registration number) were recorded. All
samples were analysed before the expiry dates.
Standards and stocks solution
Artemether-lumefantrine
Ion pair reagent solution: this was prepared by dissolving 5.65 g
of sodium hexane sulphonate and 2.75 g of potassium dihydro-
gen phosphate in distilled water and made up to 1 L with water.
The pH of the solution was adjusted to 2.3 using phosphoric
acid.
The diluent: this was prepared by mixing ion pair reagents
solution, water, 1-propanol and acetonitrile in the ratio 2.0: 0.6:
2.0: 5.4, respectively.
Dissolution medium for lumefantrine: 10 g of benzalkonium
chloride was dissolved in 500 ml 0.1 M HCl and made up to 1 L
with distilled water.
Lumefantrine reference standard (RS) stock solution (dissol-
ution test): lumefantrine (0.18 g) was dissolved in a 250 ml volu-
metric flask containing dissolution medium for lumefantrine.
Artemether-lumefantrine RS stock solution (assay): this was
prepared by dissolving 20 mg artemether RS and 120 mg lume-
fantrine RS into a 100 ml volumetric flask and made up to vol-
ume using the diluents.
Artemether RS stock solution (dissolution test): artemether
RS (20 mg) was dissolved in 100 ml of a solvent containing a
mixture of water and acetonitrile (1:1).
Artesunate
Artesunate RS stock solution (assay): artesunate RS (40 mg) was
dissolved in 10 ml of acetonitrile.
Artesunate RS stock solution (dissolution test): artesunate RS
(10 mg) was dissolved in 25 ml of 1 N sodium hydroxide in a
250 ml volumetric flask and made up to volume with water.
Sample preparation for assay
Artemether-lumefantrine: 20 tablets of each of the brands were
selected at random, weighed, and powdered. A quantity of the
powder for each brand equivalent to about 20 mg of artemether
and 120 mg of lumefantrine was accurately weighed and trans-
ferred to a 100 ml volumetric flask and made up to volume with
the diluents. The resulting solution was filtered.
Artesunate: 20 tablets of each of the brand were selected at
random, weighed and powdered. A quantity of the powder
equivalent to about 40 mg of artesunate was accurately
weighed and shaken with 10 ml of acetonitrile for 15 minutes.
The resulting solution was filtered.
91
O. Izevbekhai et al.
Analytical procedures
Uniformity of weight
The uniformity of weight of each brand of artesunate and
artemether-lumefantrine was assessed using the International
Pharmacopoeia method for uniformity of weight for single-dose
preparations.11
Identification test: thin layer chromatographic (TLC) analysis
A mixture containing 40 ml of hexane and 10 ml of ethyl acet-
ate was used as the mobile phase. Each of the following solu-
tions in acetone was spotted separately on the plate.
Solution A: a quantity of powdered tablet containing about
10 mg of artemether (60 mg of lumefantrine) was shaken for
5 min with 10 ml of acetone, filtered and the clear filtrate was
used.
Solution B: 10 mg of Artemether RS and 60 mg of
Lumefantrine RS were shaken with 10 ml of acetone. The fil-
trates of the powdered tablets and the reference standard
solution were spotted on silica gel plate and air dried for
about 3–5 min before development. The spots were located
by visual inspection and examination under ultra violet light
(254 nm). The plate was then sprayed with a sulphuric acid-
methanol mixture, heated for 10 min at 1400°C and exam-
ined in daylight.
Dissolution test
Artemether: one tablet was put into each of the six vessels of
the dissolution rate apparatus with distilled water as the dis-
solution medium at 370°C at 100 rpm. Aliquots of the medium
were taken at 1 h and 3 h and filtered into appropriately
labelled vessels. This procedure was repeated for each of the
10 brands used. The amount dissolved was then determined
using liquid chromatography by injecting 20 μl each of the
standard artemether solution and dissolution filtrate separ-
ately into the liquid chromatographic system and eluted with
a mobile phase consisting of acetonitrile, water, 1-propanol
and trifluoroacetic acid in ratio 5:4:0.99:0.01 at a flow rate of
1 ml per minute and monitored at 210 nm. The procedure
was repeated in triplicate and the average peak response
determined.
The percentage of artemether dissolved was then calculated
as stated in the United States Pharmacopoeia (USP)11 using the
formula below.
(ru*Cs*1000*100)
Artemether dissolved (%)=
(rs*L)
ru=peak response obtained from test solution, rs=peak response
obtained from standard solution, Cs=concentration (in mg/ml) of
artemether in standard solution, 1000 is the volume in ml of
medium, 100 is conversion factor to percentage, L is tablet label
claim for artemether in mg.
Assay procedure
Artemether-lumefantrine: 20 μl of the standard solution of
artemether and lumefantrine and that of each of the samples
92
was injected into the liquid chromatographic system with the
mobile phase consisting of acetonitrile and ion pair reagents
(70:30) at a flow rate of 1.3 ml per minute and at a wave-
length of 210 nm for the first 5 min and programmed to
380 nm for the remaining 6 min. The procedure was repeated
in triplicate for each of the brands and average peak response
determined.
The quantity of artemether and lumefantrine in the portion
of the tablets taken was calculated using the formula:
⎛ ru ⎞
Q (Quantity)=C*V ⎜ ⎟
⎝ rs ⎠
where, C=concentration in mg/ml of the appropriate reference
standard, V=volume in ml of the assay preparation (100 ml),
ru=peak response of the corresponding analyte peak obtained
from assay preparation, rs=peak response of corresponding ana-
lyte peak obtained from the standard preparation.
Artesunate: 20 μl of the standard solution of artesunate and
that of each of the samples were separately injected into the
liquid chromatographic system with the mobile phase consisting
of acetonitrile and potassium dihydrogen phosphate (KH2PO4)
buffer (pH 3.0) (50:50) at a flow rate of 0.6 ml per minute and
monitored at 216 nm at 300 C. The procedure was repeated in
triplicate for each of the brands and the average peak response
determined.
Specificity study
The specificity of the method was assessed by injecting the
same concentrations of reference standards for different anti-
malarial drugs such as quinine, amodiaquine, dihydroartemisi-
nin, artemether and chloroquine separately and as a mixture
into the liquid chromatographic system used, using the same
conditions as in the assay. The retention times of the drugs
were noted so as to check for possible interference with the
peaks of artemether and lumefantrine.
Results and Discussion
Description of samples
A description of the products included in the study is presented
in Table 1. All the samples are registered by the Nigerian drug
regulatory agency, NAFDAC. A total of 30 products: 10 arte-
mether/lumefantrine, 11 artesunate/amodiaquine, 2 artesu-
nate/sulphadoxine-pyrimethamine, 1 artesunate/mefloquine
and 6 artesunate monotherapy were sampled. Of these, 6 were
manufactured in China, 18 in India, four in Nigeria, 1 in the USA
and one in Vietnam. All products were analysed before their
expiry dates and the mean time to expiry was 17.5 months at
the time of analysis.
Identification and weight uniformity tests
A comparison of the TLC Rf values for the reference standard of
each drug with those of the products revealed that all of them
contained the active ingredients stated on the label. Using a
percentage deviation of ±5% from the mean weight for a
Transactions of the Royal Society of Tropical Medicine and Hygiene

Table 1. Description of samples of artemisinin-based antimalarial tablets

Code Components (mg) Batch no. Man. date Expiry date NAFDAC no. Country of manufacturing

AL 1 Artemether (20)/Lumefantrine (120) AMMH0009 Jan-09 Dec-11 A4-1888 India

AL 2 Artemether (20)/Lumefantrine (120) 8K563002 Oct-08 Sep-10 A4-2180 Nigeria
AL 3 Artemether (20)/Lumefantrine (120) LL803 Jun-08 May-10 A4-0269 India
AL 4 Artemether (20)/Lumefantrine (120) 680226 Aug-08 Jul-11 A4-1695 India
AL 5 Artemether (20)/Lumefantrine (120) 80610 Jun-08 Jun-11 A4-1414 China
AL 6 Artemether(20)/Lumefantrine (120) CM 901 Jan-09 Dec-10 A4-2130 India
AL 7 Artemether (20)/Lumefantrine (120) F0007 Oct-08 Sep-10 Apr-75 USA
AL 8 Artemether (20)/Lumefantrine (120) LN-35 Aug-08 Jul-10 Apr-69 India
AL 9 Artemether (20)/Lumefantrine (120) NP803 Jun-08 May-11 A4-0413 India
AL 10 Artemether (40)/Lumefantrine (240) 80116 Jan-08 Jan-11 A4-0622 China
AS 1 Artesunate (50)/Amodiaquine (200) 470799 Sep-07 Aug-09 Apr-97 India
AS 2 Artesunate (200)/Amodiaquine (600) 70110 Jan-07 Jan-10 Apr-59 China
AS 3 Artesunate (100)/Sulphadoxine/ APKH0005 Oct-07 Sep-10 Apr-04 India
pyrimethamine (500/25)
AS 4 Artesunate (50)/Amodiaquine (150) 70808 Aug-08 Jul-11 Apr-56 China
AS 5 Artesunate (100)/Sulphadoxine/ 50908 Sep-08 Aug-11 Apr-89 China
pyrimethamine (500/25)
AS 6 Artesunate (100) G0-14 Mar-07 Feb-10 Apr-25 India
AS 7 Artesunate (50) TVAS07 Aug-08 Jul-11 Apr-74 Nigeria
AS 8 Artesunate (50) 08037FX Oct-08 Oct-11 Apr-97 Vietnam
AS 9 Artesunate (50) NA009 Sep-08 Not stated Apr-43 India
AS 10 Artesunate (200)/Mefloquine (250) NT001 Aug-07 Jul-10 A4-0414 India
AS 11 Artesunate (200)/Amodiaquine (612) NB001 Aug-07 Jul-10 A4-0432 India
AS 12 Artesunate (50)/Amodiaquine (150) KW8601 May-08 Apr-10 Apr-22 India
AS 13 Artesunate (100)/Amodiaquine (300) ATAH 0004 Oct-08 Sep-11 Apr-50 India
AS 14 Artesunate (50)/Amodiaquine (150) VU801 Jan-08 Dec-09 Apr-13 India
AS 15 Artesunate (50)/Amodiaquine (150) 06-007 Oct-06 Oct-09 Apr-86 Nigeria
AS 16 Artesunate (50)/Amodiaquine (150) BDV8006F Jun-08 May-11 Apr-54 India
AS 17 Artesunate (50)/Amodiaquine (150) 2313M May-08 May-11 A4-0243 Nigeria
AS 18 Artesunate (50) 80727 Jul-08 Jul-11 Apr-37 China
AS 19 Artesunate (50) ARD702 Jul-07 Jun-10 Apr-13 India
AS 20 Artesunate (100)/Amodiaquine (300) M070520 May-07 Apr-10 Apr-08 India

Man: manufacturing.
A total of 10 artemether/lumefantrine, 11 artesunate/amodiaquine, 2 artesunate/sulphadoxine-pyrimethamine, 1 artesunate/mefloquine and
6 artesunate monotherapy products were sampled.

minimum of 18 tablets as cut-off for tablets with average
weight >250 mg, three products AL 2, AS 5 and AS 19 did not
meet the IP requirement for weight uniformity.11
Assay and dissolution test
Artemether-lumefantrine
The retention times for artemether and lumefantrine were 2.7 and
10.12 min, respectively, and the peaks were very well resolved
(Figure 2). The method is also specific in the separation of
artemether-lumefantrine from amodiaquine, artesunate, dihydroar-
temisinin, chloroquine and quinine. A total of 10 brands of
artemether-lumefantrine tablets were analysed and they contained
91–103% of artemether and 52–100% of lumefantrine. All the 10
brands met the assay requirement of 90–110% for artemether.
However, two samples (AL 6 and AL 10) did not meet the assay
requirements for lumefantrine.
For the dissolution test, the artemether tablets were
expected to release ‘not less than 45% of the labelled amount
in 1 h and not less than 65% of the labelled amount in 3 h’
(USP:2009).11 Only four of the 10 brands used in this study met
this requirement. One of the samples (AL 3) did not even release
the active ingredient at all while five others (AL 1, AL 4, AL 6, AL
9 and AL 10) released the active ingredient in quantities that fell
below the amount specified. The median (range) artemether
component released in the first 1 hour and in 3 hours were 46%
(23–47%) and 62% (43–69), respectively (Table 2).

93
O. Izevbekhai et al.

Artesunate In a previous assessment, Esimone et al. reported that only 4

The retention time of artesunate was 7.2 minutes. The median
artesunate composition in the twenty artesunate-containing
brands analysed was 96% (84–107%). Five brands (AS 4, AS 10,
AS 11, AS 15 and AS 19) failed to meet the requirement that
artesunate tablets contain not less than 90% and not more
than 110% of the amount stated on the label. It will be noted
that two of these samples (AS 5 and AS 19) also failed the
weight uniformity test (Table 3).
Overall, only about 77% of the artemisinin products included
in the present study met the standard assay requirements. All
10 brands (100%) of the artemether-lumefantrine tablets met
the assay requirement for artemether and 8 (80%) met the
assay requirement for lumefantrine. But only four brands (40%)
met the requirement for artemether dissolution. Of the 20
brands of artesunate-containing brands included in this study,
15 (75%) met the standard assay requirement for artesunate.
Figure 2. A typical chromatogram showing separation of artemether (A)
and lumefantrine (L).
out of 9 (44%) brands of artesunate in Nigeria met standard
assay requirements.13 An assessment of the quality of antimal-
arial drugs in Ghana revealed important quality deficiencies with
a failure rate of 35% (16 of a total of 45 antimalarial samples
analyzed). Four of the 12 artemisinin derivatives included in the
study (33%) failed to meet standard specifications.14 In a quali-
tative study reported by Newton et al. of 104 artesunate sam-
ples from Cambodia, Laos, Myanmar (Burma), Thailand and
Vietnam, 38% did not contain artesunate.8 In a nationwide sur-
vey of antimalarial drugs in Tanzania by Kaur et al,15 38 brands
of artemisinin derivative were analysed in the absence of an
official monograph for the dissolution profile of artemisinin deri-
vatives. In this report, the tablets were crushed, dissolved in
methanol and an aliquot of the resulting solution was then ana-
lysed. In our own opinion, this method can hardly be used as a
basis for the conclusion reached by the authors that ‘no artemisi-
nin products failed the quality testing’.15 In a review of antimalar-
ial drug quality in Africa, Amin et al. reported that out of the 48
studies reviewed, 31 (65%) concluded that more than 80% of
samples analysed (sulfadoxine–pyrimethamine, quinine, progua-
nil, Mefloquine, chloroquine and amodiaquine) had the right
amount of the active ingredient.16 The situation does not appear
to be different for artemisinin derivatives, which are now used as
first-line therapy in countries with the highest burden of malaria.
As alarming as this may sound, it is not conclusive since many
more of the samples may still fail the dissolution test.
There is evidence to suggest an overlap in the widespread
use of substandard and counterfeit artemisinins and the emer-
gence of P. falciparum resistance to these drugs. For instance,
Newton et al. and Rozendaal et al. both reported the presence
of counterfeit and substandard artemisinin derivatives in parts
of Asia.5,7 The emergence of P. falciparum resistant to the arte-
misinins was later reported in these areas. Dondorp et al. also
reported reduced in vivo susceptibility of P. falciparum to

Table 2. Identification test, weight uniformity test, assay and dissolution test for artemether-lumefantrine brands

Sample code Identity Weight uniformity test Assay Dissolution test

Artemether Lumefantrine % artemether dissolved in 1 hr % artemether dissolved in 3 hrs

AL 1 M M 97.91 95.63 45.9 61.8

AL 2 M F 103.12 92.78 45.9 66.9
AL 3 M M 97.89 99.99 0 0
AL 4 M M 97.21 94.47 46.0 61.1
AL 5 M M 98.59 97.99 45.8 69.1
AL 6 M M 99.25 88.43 29.5 43.2
AL 7 M M 95.18 95.59 57.8 68.2
AL 8 M M 91.19 92.71 47.4 67.0
AL 9 M M 101.84 90.45 23.1 45.7
AL 10 M M 91.94 52.44 39.8 54.3

M: met standard requirements; F: failed.

All 10 brands met the assay requirement for 90–110% of artemether but 2, AL6 and AL10 containing 88.4 and 52.4%, respectively, failed. A
total of 6 brands (AL1, AL 3, AL4, AL6, AL9, and AL10) did not meet dissolution test requirement.

94
Transactions of the Royal Society of Tropical Medicine and Hygiene

Conclusions
Table 3. Identification test, weight uniformity test and assay for The presence of poor quality artemisinin-based antimalarials in
artesunate-containing brands Nigeria, as in other parts of Africa, is real and constitutes a
major threat to public health with many devastating conse-
Sample code Identity Weight uniformity test Artesunate quences for patients (increased mortality and morbidity) and
represents a potential route for resistance to these drugs in the
AS 1 M M 97.8 future. Every malaria patient treated with substandard
AS 2 M M 96.5 artemisinin-based therapy is in danger of progressing to severe
AS 3 M M 97 illness and in some cases of dying.
AS 4 M M 88.8 The presence, on a wider scale, of counterfeit and substand-
AS 5 M F 97.8 ard artemisinins in the market may precipitate a collapse of
AS 6 M M 94.8 confidence in the artemisinin-based therapy. The inclusion of
AS 7 M M 93.5 antimalarial drug quality monitoring as part of comprehensive
AS 8 M M 100 disease surveillance programmes would be a good way to pre-
AS 9 M M 90.5 vent widespread distribution and use of counterfeit and sub-
AS 10 M M 89.2 standard artemisinin drugs.22 With no alternatives to replace
AS 11 M M 87.3 the artemisinins in the event of widespread resistance, this
AS 12 M M 102.7 appears to be the only way to extend their life-span.
AS 13 M M 103.8
AS 14 M M 106.8
AS 15 M M 84.1
AS 16 M M 95.8
AS 17 M M 92.6
AS 18 M M 95.4 Authors’ contributions: AO carried out the assay of artesunate-
AS 19 M F 89.6 containing antimalarial brands. OI carried out the assay and dissolution
tests of artemether-lumefantrine brands. AO and BA drafted the manu-
AS 20 M M 97.9
script. OB and BA conceived and supervised the project. All authors read
and approved the final manuscript. OB and BA are the guarantors of the
M: met standard requirements; F: failed. paper.
The median artesunate composition was 96 (84, 107)%. Five
brands (AS 4, AS 10, AS 11, AS 15 and AS19) failed to meet the
Acknowledgements: The authors acknowledge the support of Carnegie
requirement that artesunate tablets contain not less than 90% and
Corporation of New York, USA, for the support given to the Central
not more than 110% of the amount stated on the label.
Science Laboratory and the Therapeutic Drug Monitoring Laboratory of
Obafemi Awolowo University and Obafemi Awolowo University Teaching
Hospital Complex, respectively, where the study took place.

artesunate in western Cambodia in two open-label, randomised Funding: None.

trials comparing the efficacies of two treatments for uncompli-
cated falciparum malaria in Pailin, western Cambodia and Wang
Pha, northwestern Thailand.17
Resistance to artemisinins could spread to other parts of the
world and this could pose a major public health challenge as
there is currently no alternative antimalarial medication that is
as efficacious and as tolerable as ACTs.18 The spread of resist-
ance could occur because front-line antimalarial regimen in
some parts of Africa doesn’t clear parasitaemia completely and
this leads to uptake of parasites that have been exposed to
drugs by mosquitoes.19 The inability of antimalarials to com-
pletely clear parasitaemia could be as a result of the use of
counterfeit or falsified drugs which in turn could lead to selec-
tion of and spread of resistant parasites.20
Newton et al., in their paper, examined the relationship
between poor quality antimalarials and malaria drug resistance
and concluded that low quality antimalarials, artemisinins inclu-
sive, could aid the selection of drug resistant pathogens.
Resistant parasites will, therefore, have an advantage when they
come in contact with low quality medications, in that they will
have a higher chance of survival and therefore multiply faster
and for poor quality ACTs, resistance could also spread to the
partner drug thereby posing a huge public health problem.21
Competing interests: None declared.
Ethical approval: Not required.
References
1 WHO, UNICEF. Achieving the malaria MDG target: Reversing the inci-
dence of malaria 2000–2015. Geneva: World Health Organization;
2015
2 Federal Ministry of Health. A Road Map for Impact on Malaria in
Nigeria: Rapid Scale up of Malaria Control Interventions for Impact in
Nigeria. 2006. http://www.rollbackmalaria.org/countryaction/nsp/
nigeria.pdf [accessed 3 June 2013].
3 WHO. World Malaria Report. Geneva: World Health Organization; 2012.
http://www.who.int/entity/malaria/publications/world_malaria_report_
2012/wmr2012_full_report.pdf [accessed 1 April 2013].
4 Thanh NV, Toan TQ, Cowman AF et al. Monitoring for Plasmodium fal-
ciparum drug resistance to artemisinin and artesunate in Binh Phuoc
Province, Vietnam: 1998–2009. Malar J 2010;9:181.
5 Rozendaal J. Fake antimalaria drugs in Cambodia. Lancet 2001;
357:890.

95
O. Izevbekhai et al.
6 Kelesidis T, Kelesidis I, Rafailidis PI, Falagas ME. Counterfeit or sub-
standard antimicrobial drugs: a review of the scientific evidence.
J Antimicrob Chemother 2007;60:214–36.
7 WHO. Malaria Fact Sheet. Geneva: World Health Organization; 2013.
http://www.who.int/mediacentre/factsheets/fs094/en/ [accessed 27
March 2013].
8 Newton P, Proux S, Green M et al. Fake artesunate in southeast Asia.
Lancet 2001;357:1948–50.
9 Anthony MP, Burrows JN, Duparc S et al. The global pipeline of new
medicines for the control and elimination of malaria. Malar J 2012;
11:316.
10 Menard D, Matsika-Claquin MD, Djalle D et al. Association of failures
of seven-day courses of artesunate in a non-immune population in
Bangui, Central African Republic with decreased sensitivity of
Plasmodium falciparum. Am J Trop Med Hyg 2005;73:616–21.
11 The United States Pharmacopoeia XXXII and The National Formulary.
First supplement. Stage 6 Harmonization. 27th ed. Rockville, MD: The
United States Pharmacopoeia Convention, Inc.; 2011;(905):1–3.
12 WHO. Artemether and Lumefantrine Tablets. The International
Pharmacopoeia. 4th ed. Vol. 4 Geneva: World Health Organization;
2011, p. 1–5.
13 Esimone CO, Okoye FB, Onah BU et al. In vitro bioequivalence study
of nine brands of artesunate tablets marketed in Nigeria. J Vector
Borne Dis 2008;45:60–5.
96
View publication stats
14 Tetteh G, Botwe B, Gyimah P. Assessment of the availability and
quality of antimalarials in the public and private sectors of Ghana.
Management Sciences for Health, Rational Pharmaceutical
Management Plus Program, US AID; 2006:1-45.
15 Kaur H, Goodman C, Thompson E et al. A nationwide survey of the
quality of antimalarials in retail outlets in Tanzania. PloS One 2008;3:
e3403.
16 Amin AA, Kokwaro GO. Antimalarial drug quality in Africa. J Clin
Pharm Ther 2007;32:429–40.
17 Dondorp AM, Nosten F, Yi P et al. Artemisinin resistance in
Plasmodium falciparum malaria. N Engl J Med 2009;361:455–67.
18 WHO. Malaria. Q&A on artemisinin resistance. Geneva: World Health
Organization; 2016. http://www.who.int/malaria/media/artemisinin_
resistance_qa/en/ [accessed 28 February 2017].
19 Sutherland CJ. Rescuing artemisinin combination therapy in Africa.
Lancet 2017;5:8–9.
20 Johnston A and Holt DW. Substandard drugs: a potential crisis for
public health. Br J Clin Pharmacol 2013;78:218–43.
21 Newton PN, Caillet C and Guerin PJ. A link between poor quality anti-
malarials and malaria drug resistance? Expert Rev Anti Infect Ther
2016;14:531–3.
22 Green MD. Antimalarial drug resistance and the importance of drug
quality monitoring. J Postgrad Med 2006;52:288–90.