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Table of Contents
ORIGINAL ARTICLES
Year : 2021  |  Volume : 26  |  Issue : 3  |  Page : 175-182

Impact of two anti-malaria drugs (artequin and chloroquine) on some hematological parameters in wistar rats


1 Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus, Nigeria
2 Department of Ophthalmology, Enugu State University Teaching Hospital, Parklane-Enugu, Nigeria
3 Department of Physiology, College of Medical Sciences, University of Calabar, Nigeria

Date of Submission06-Aug-2020
Date of Decision24-Aug-2020
Date of Acceptance24-Jan-2021
Date of Web Publication20-Apr-2021

Correspondence Address:
Princewill Ikechukwu Ugwu
Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus,
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmh.IJMH_53_20

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  Abstract 

Background: Artequin (AQ) and other Artemisinin-based therapies have replaced chloroquine (CQ) as the preferred treatment for uncomplicated Plasmodium falciparum malaria, due to the resistance of the parasite to CQ. This study was designed to investigate the comparative effects of CQ and AQ on some haematological parameters in Wistar rats. Materials and Methods: Thirty-six (36) female Wistar rats were randomly assigned into two batches. Each batch had three groups of six rats each, and they were placed on normal rat chow: AQ (1.6mg/100g bwt) and/or CQ (0.875mg/100g bwt) orally and once daily for three and seven days for batches 1 and 2, respectively. Full blood count was carried out by using an automated blood cell counter. Results: Results showed that the administration of AQ for three days did not significantly alter the levels of red blood cells (RBCs), RBC indices, hemoglobin (Hb), packed cell volume (PCV), total and differential white blood cells (WBCs), platelet count, and platelet indices. However, CQ increased the RBCs, Hb, PCV, and eosinophils significantly (P < 0.05) compared with the control. CQ also increased the total WBCs significantly (P < 0.05) compared with AQ. Both drugs decreased neutrophil but increased lymphocyte count significantly (P < 0.05) compared with the control after three days of treatment. After seven days of administration, AQ significantly (P < 0.05) reduced RBC count, PCV, Hb, mean corpuscular hemoglobin concentration (MCHC), and neutrophils compared with the control; both drugs reduced platelet count and PCT significantly (P < 0.05) compared with the control after seven days of treatment. Conclusion: The administration of AQ or CQ at their recommended doses and duration is relatively safe. However, administering a combination of Artesunate and mefloquine, and not CQ, beyond normal duration might have negative effects on hematological parameters.

Keywords: Artesunate, blood cells, chloroquine, mefloquine, wistar rats


How to cite this article:
Ugwu PI, Anyaehie UB, Ugwu AO, Ofem OE. Impact of two anti-malaria drugs (artequin and chloroquine) on some hematological parameters in wistar rats. Int J Med Health Dev 2021;26:175-82

How to cite this URL:
Ugwu PI, Anyaehie UB, Ugwu AO, Ofem OE. Impact of two anti-malaria drugs (artequin and chloroquine) on some hematological parameters in wistar rats. Int J Med Health Dev [serial online] 2021 [cited 2021 Dec 9];26:175-82. Available from: https://www.ijmhdev.com/text.asp?2021/26/3/175/313953




  Introduction Top


The indiscriminate use of anti-malaria drugs has become a norm in Nigeria. Anti-malaria drugs are available as over-the-counter medications and are hence easily accessible to users with and without prescription. This phenomenon is attributed to a number of factors. Malaria symptoms mimic a number of other diseases. Conversely, a patient with any febrile illness, or even a malaise that might just be stress induced, is many a time misdiagnosed with malaria. Misdiagnosed patients end up using anti-malaria medications unnecessarily. Another is the emergence of drug-resistant strains of the parasites that cause malaria. Old drugs used as first-line treatment in the past, such as CQ, quinine, and sulfadoxine-pyrimethamine, have been replaced with new drugs. This change is as a result of the development of resistance by the malaria parasites and some adverse effects experienced by some individuals on administration of the old drugs.[1],[2] In recent times, the old drugs, especially CQ [Figure 1], are again being reported as effective. It has even been reported to play a role in limiting the spread of some infectious viral diseases,[3],[4] which may lead to even more abuse of the drug.
Figure 1: Chemical structure of chloroquine

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Currently, the World Health Organization (WHO) is advocating for a change to artemisinin-based combination therapy (ACT).[5] An example of such therapies is AQ (a combination of Artesunate and mefloquine). The probability of the development of resistance by the malaria parasites to two drugs with independent mechanisms of action is very low.[6] Artesunate [Figure 2] is a natural anti-malaria drug derived from the Chinese medicinal component Artemisinin, which is obtained from the plant Artemisia annua. Artemisinin derivatives are the most effective anti-malaria drugs and have been proven to be successful against multidrug-resistant Plasmodium falciparum.[7] Mefloquine [Figure 3] is a drug that has been used for malaria chemoprophylaxis.[8] The chemical structures of the drugs are shown in [Figure 1][Figure2 ][Figure 3].[9]
Figure 2: Chemical structure of artesunate

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Figure 3: Chemical structure of mefloquine

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The WHO estimates that medicines are prescribed, dispensed, or sold inappropriately and that half of all patients fail to take them correctly. This not only undermines the potential usefulness of medicines but also results in negative therapeutics. There is increasing indiscriminate use of anti-malaria drugs, including their usage for those not diagnosed with malaria; hence, this study was designed to investigate the effects of CQ and AQ on hematological parameters in Wistar rats to ascertain their safety when used at a recommended dosage and when used beyond a recommended regimen.


  Materials and Methods Top


Experimental animals

Thirty-six (36) female Wistar rats weighing between 180 and 240g were obtained from the animal house of the Physiology Department, University of Uyo, Nigeria. They were housed in well-ventilated cages under room temperature (28 ± 2°C) and humidity of 85 ± 5%. The animals were exposed to a normal 12/12 light/dark cycle and allowed to acclimatize for seven days before drug administration was started. The rats had access to normal chow and drinking water ad libitum. The rats were handled in accordance with internationally accepted principles for laboratory animal use and care as found in the European Community guidelines (EEC Directive of 1986; 86/609/EEC).

Drug preparation and administration

CQ (150 mg) which was manufactured by Evans Medical Plc, Agbara, Ogun State, Nigeria, and AQ (600/750 mg) which was packaged in Nigeria by Oculus Pharmacare Limited, Mushin, Lagos for Mepha Pharma AG, Aesch, Switzerland, were used for this experiment. The drugs were bought at Amela Pharmacy, Oron Road, Uyo, Nigeria. It was stored in a cold dry cabinet at controlled temperature at the research room of the Department of Physiology, University of Uyo.

One tablet each of Artesunate (200mg) and Mefloquine (250mg), which constitute AQ (450mg), were crushed together by using a ceramic mortar and pestle; then, they were dissolved in a total of 45ml of distilled water to give a concentration of 10mg/mL stock. The drug combination was administered to the animals at a dose of 0.64mg/100g body weight [equivalent to human (70kg) daily dose], that is, 0.06mL of stock/100g body weight.

One tablet of CQ (150mg) was ground to powder and dissolved in a total of 20mL of distilled water to give a stock concentration of 7.5mg/mL. The drug was first administered at a dose of 0.857mg/100g body weight (i.e. 0.11mL of stock/100g body weight) for the first two days. On the third day and subsequent days, 0.429mg/100g body weight (i.e., 0.06mL of stock/100g body weight) was administered.

After every administration, the remaining drug was discarded and a new one was prepared for the next administration.

Experimental design

The rats were divided into two batches. Each batch had three groups of six rats each. Group 1 was control, whereas groups 2 and 3 were AQ- and CQ-treated groups, respectively. The treatment lasted for three and seven days for batches 1 and 2, respectively. All animals had free access to normal rat chow and drinking water.

Blood sample collection

After the days of drug administration elapsed, the rats were sacrificed and blood samples were obtained by cardiac puncture under chloroform anesthesia, a modification by Ohwada (1986).[10] A quick dissection was made on the thoracic region to expose the heart. The left ventricle was pierced with a needle syringe (25 gauge), and blood was taken by slow aspiration. About 3mL of the blood obtained was emptied into a 5-mL EDTA-capped sample that was bottled for analysis of blood parameters.

Measurement of blood parameters

Blood samples were analyzed by using an automated cell counter (Coulter Electronics, Luton, Bedfordshire, UK) with standard calibration using normal human blood and with complete profile for RBC count, WBC count, Hb, PCV, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCHC, red blood cell distribution width (RDW), mean platelet volume (MPV), and platelet distribution width (PDW).

Data analysis

Data were analyzed as mean ± SEM; they were analyzed by using a one-way analysis of variance (ANOVA). Significant values were processed with least significant difference (LSP). A P value of <0.05 was declared as being statistically significant. Data were analyzed by using Statistical Package for the Social Sciences (SPSS) software program, version 20.0 (IBM, Chicago, IL, USA).


  Results Top


Effects of CQ and AQ on RBCs and RBC indices

[Table 1] shows the results for the MCV (fL) on days 3 and 7. No significant differences were observed in MCV (fL) among the different groups on day 3. On day 7, values were significantly (P < 0.05) lower in the CQ group (58.65 ± 0.82 fL) compared with the control (62.09 ± 0.83 fL) and AQ (61.14 ± 1.11 fL).
Table 1: Comparison of RBC and platelet indices in control, AQ- and CQ-treated groups

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Results for MCH (pg) are also presented in [Table 1]. The MCH values in control, AQ, and CQ groups on day 3 were 18.92 ± 0.37 pg, 19.07 ± 0.14 pg, and 18.75 ± 0.06 pg, respectively. On day 7 of administering drugs, the values of MCH in the groups were 19.52 ± 0.38 pg, 18.56 ± 0.19 pg, and 18.42 ± 0.20 pg, respectively. No significant differences were observed in MCH among the different groups on day 3, but on day 7 values in AQ and CQ reduced significantly (P < 0.05) compared with the control.

MCHC (g/dL) was not significantly different among the different experimental groups on day 3. The AQ group had significantly lower values (30.40 ± 0.29g/dL) compared with the control (31.44 ± 0.26g/dL) and CQ (31.40 ± 0.22g/dL) on day 7 of the experiment [Table 1].

After the experiment, the RBC count of the control, AQ, and CQ administered groups was 6.68 ± 0.19 × 1012 cells/L, 6.95 ± 0.14 × 1012 cells/L, and 7.50 ± 0.22 × 1012 cells/L, respectively, after three days of treatment, showing significantly raised values in the CQ group (P < 0.05) compared with the control. After seven days of treatment, values in the control, AQ, and CQ groups were 7.27 ± 0.18 × 1012 cells/L, 6.78 ± 0.12 × 1012 cells/L, and 7.82 ± 0.22 × 1012 cells/L, respectively, showing a significant (P < 0.05) reduction in the AQ compared with the control and CQ groups. These are seen in the first figure given next [Figure 4].
Figure 4: Comparison of RBC count between the different control, AQ- and CQ-treated groups at days 3 and 7. Values are expressed as mean ±SEM, n = 6. * = significant at P < 0.05 vs control. a = significant at P < 0.05 vs artequin

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In [Figure 5], the mean Hb concentrations in the control, AQ, and CQ groups after three days were 12.23 ± 0.30g/dL, 13.07 ± 0.30g/dL, and 14.67 ± 0.94g/dL, respectively, showing a significant increase in the CQ group (P < 0.05) compared with the control. On day 7, the values were 14.17 ± 0.24g/dL, 12.58 ± 0.31g/dL, and 14.337 ± 0.47g/dL, respectively, showing a significant decrease in the AQ group (P < 0.01) compared with the control and CQ groups.
Figure 5: Comparison of Hb concentration between the different control, AQ- and CQ-treated groups at days 3 and 7. Values are expressed as mean ± SEM, n = 6. *P < 0.05, **P < 0.01 vs control

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After three days of drug administration, the mean PCV (%) in CQ (47.23 ± 3.48) was also significantly increased (P < 0.05) compared with the control (38.93 ± 1.23). On day 7, PCV was significantly reduced (P < 0.05) in the AQ group (41.45 ± 1.11) compared with the control (45.08 ± 0.63) and CQ groups (45.93 ± 1.68) [Figure 6].
Figure 6: Comparison of PCV between the different control, AQ- and CQ-treated groups at days 3 and 7. Values are expressed as mean ± SEM, n = 6. *P < 0.05 vs control. a = P < 0.05 vs artequin

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Effect of CQ and AQ on platelet count and platelet indices

The platelet count (×109 platelets/L) on day 3 was not significantly different among the different experimental groups. However, on day 7, values in AQ (792.33 ± 35.48) and CQ (941.67 ± 41.31) were significantly (P < 0.05) lower compared with the control (1251.00 ± 165.32); see [Figure 7].
Figure 7: Comparison of platelet count between the different control, AQ- and CQ-treated groups at days 3 and 7. Values are expressed as mean ± SEM, n = 6. *P < 0.05 vs control. a = P < 0.05 vs artequin

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There were no significant statistical differences observed in MPV among the different experimental groups on day 3 and on day 7 of the experiment. Values in controls were 6.17 ±0.14 and 6.27 ±0.18 on days 3 and 7, respectively; see [Table 1].

PDW was also not significantly different among the different experimental groups on days 3 and 7. Control values were 15.50 ± 0.10 and 15.08 ± 0.09 on days 3 and 7, respectively; see [Table 2].
Table 2: Comparison of differential WBC count in control, AQ- and CQ-treated groups

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Plateletocrit (PCT) on day 3 did not differ significantly among the different experimental groups. On day 7, however, values obtained in the AQ group (4.96 ± 0.23%) were significantly (P < 0.01) lower compared with the control and CQ groups; see Table 1.

Effect of CQ and AQ on total and differential WBC counts

After three days of treatment, the total WBC count in the control, AQ, and CQ groups was 11.94 ± 0.89 × 1012 cells/L, 10.83 ± 0.85 × 1012 cells/L, and 14.18 ± 1.25 × 1012 cells/L, respectively. This reflects a significant (P < 0.05) increase in the CQ group compared with the AQ group. On day 7, no significant differences were observed among the different groups. Values were 15.98 ± 1.72 × 1012 cells/L, 15.39 ± 1.40 × 1012 cells/L, and 16.59 ± 0.71 × 1012 cells/L for the control, AQ, and CQ groups, respectively, as seen in [Figure 8].
Figure 8: Comparison of total WBC count between the different control, AQ- and CQ-treated groups at days 3 and 7. Values are expressed as mean ± SEM, n = 6. a = P < 0.05 vs artequin

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[Table 2] shows the results on neutrophil count on days 3 and 7. On day 3, significant (P < 0.05) reductions were observed in the AQ (18.45 ± 1.43%) and CQ groups (18.27 ± 0.64%) compared with the control (26.15 ± 2.48%). However, on day 7, it was significantly (P < 0.01) reduced in the AQ group compared with the CQ group.

The lymphocyte counts for the control, AQ, and CQ groups were 66.98 ± 2.05%, 73.85 ± 1.54%, and 75.22 ± 1.07%, respectively, showing a significant (P < 0.05 and P < 0.01) increase in the AQ and CQ groups compared with the control. As seen in [Table 2], values were significantly (P < 0.01) higher in the AQ group than in the control and CQ groups on day 7.

Monocyte count in the control, AQ, and CQ groups was not significantly different from each other on day 3. On day 7, values obtained for the CQ group (3.93 ± 0.55%) were significantly (P < 0.05) lower compared with the control (5.77 ± 0.37%). The AQ group had a value of 5.60 ± 1.10%, which did not differ significantly from the control or CQ group; see [Table 2].

Eosinophil count increased significantly (P < 0.05) in the CQ group (1.80 ± 0.27%) compared with the control (1.12 ± 0.33%) on day 3; however, on day 7, it decreased significantly (P < 0.05) in the CQ group compared with the AQ group, as seen in [Table 2].

Also, in [Table 2], no significant differences were observed in basophil count among the different groups on days 3 and 7.


  Discussion Top


In this study, scenarios where anti-malarial medications are taken by people who do not actually have malaria were explored. The study drugs were given to a group following the regular regimen, whereas the other group got the drugs for an extended period. The extension was to mimic real-life situations where individuals extend drug use for wrong reasons. Results obtained from this study revealed that CQ and AQ do not have tremendous or serious adverse effects on blood parameters after three days of administration, although the two drugs had variable effects on the blood parameters.

The RBC count, Hb, and PCV were significantly elevated in the CQ-administered group after three days, but after seven days of administration, no significant alterations were observed. This might be attributed to the lack of parasites in the RBCs of the rats used in the study, as CQ only gets protonated—acquiring the ability to lyse RBCs—in the presence of the digestive vacuoles of the plasmodium parasite. On the other hand, the RBC count, Hb, and PCV were significantly reduced in AQ recipients compared with the control. AQ appeared to have no deleterious effect on RBCs, Hb, and PCV when administered at the recommended dose for three days. There, however, is an indication that prolonged administration of the combination of Artesunate and Mefloquine would possibly lead to anemia. This is in consonance with both the documented pharmacology of artemisinins and reports from preclinical data, suggesting that repeated or prolonged exposure to ACT drugs may affect blood cell counts and predispose one to anemia.[11]

The increase in RBC count, Hb, and PCV observed in the CQ-administered group after three days is in contrast to the results obtained by other researchers, which indicated no changes or reduction in RBC parameters. For instance, one report asserted reductions in RBC, Hb, and anemic tendency after CQ administration, whereas another report did not observe any significant alterations in RBC count and indices when CQ was administered at the recommended duration of three days.[12],[13] This deviation from some previous studies stimulates a need for verification of mechanisms. However, our finding could be beneficial in cushioning the anemic conditions that are often associated with malaria.

Administration of these anti-malaria drugs for three days did not alter the values of MCV, MCH, and MCHC significantly; however, after seven days of administration, significant reductions in MCV and MCHC were observed. This is a possible indication that prolonged administration (for more than three days) of AQ and CQ could lead to a microcytic variety of anemia.

The total WBC (leukocyte) and lymphocyte count was significantly increased, whereas neutrophil count was significantly reduced in the CQ-treated group after three days of administration. Our finding is at variance with an earlier report in which CQ had no significant effect on WBCs throughout the duration of administration.[14] However, another report has it that an ACT drug, Coartem, increases total WBC and lymphocyte count but it decreases neutrophil count; they attributed these changes to the immunological response induced by the drug.[13],[15]

Platelets play an important role in the integrity of normal homeostasis; MPV is an indicator for its functions,[16] including aggregation, release of thromboxane A2, platelet factor 4, β-thromboglobulin,[17] and expression of glycogen 1b and glycogen IIb/IIIa receptors.[18],[19]

In the present study, after three days of administration of CQ and AQ, no significant alterations were observed in platelet count and platelet indices. However, after seven days, platelet count and PCT reduced significantly in the AQ- and CQ-treated groups compared with the control. Hence, prolonged ingestion of these drugs could affect platelet function negatively. A work carried out in the past had reported little or no adverse effect on platelet count after CQ administration.[13] In another study, contrary to this, a low platelet count followed CQ administration, but not so with artesunate.[20] It has been reported that malaria is a major health problem in the tropics with high morbidity and mortality, and it is associated with different degrees of low platelet count with increased bleeding tendency.[21]

Platelet indices are routinely reported as part of the complete blood count, but their use is generally restricted to narrowing the differential diagnosis of anemia. It is also elevated in thrombotic thrombocytopenic purpura, a disease of unknown origin, characterized by abnormally low levels of platelets in the blood, formation of blood clot in the arterioles and capillaries of many organs, and neurological damage. MPV was not significantly altered in this study after administration of the two anti-malaria drugs. MPV a determinant of platelet function, is a newly emerging risk factor for atherothrombosis. Increase in MPV has been documented in patients with metabolic syndrome, stroke, and diabetes mellitus.[22],[23] Many studies have shown that increased MPV is one of the risk factors for myocardial infarction, cerebral ischemia, transient ischemic attacks, and chronic vascular disease.[24],[25],[26],[27],[28]


  Conclusion Top


In conclusion, the administration of AQ or CQ at their recommended duration (three days) is relatively safe. On prolonged administration, AQ (and not CQ) could predispose the body to anemia and bleeding tendencies; however, both drugs could cause thrombocytopenia when administered beyond the recommended duration of three days. This, however, may not be a demerit, as there are beneficial effects of regulation of platelet count and activity. The reality of the safety margin of CQ is quite evident in this study. More studies need to be conducted along this line to delineate such mechanisms.

Author contributions

PIU developed the concept and the initial article draft. PIU and OEO worked on the study design and also did the animal farm/laboratory work and data collection. AOU did the literature search and editing of the article. OEO and PIU did the data analysis. UBA proof read and approved the final version to be published.

Ethical clearance

Ethical approval for the study was obtained from the Ethical Committee of the College of Health Sciences, University of Uyo, Akwa Ibom State, Nigeria.

Financial support and sponsorship

The authors received no external funding for this study.

Conflict of interest

None declared.



 
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Martin JF, Bath PM, Burr ML Influence of platelet size on outcome after myocardial infarction. Lancet 1991;338:1409-11.  Back to cited text no. 17
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2]



 

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