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Aminoquinolines Against Coronavirus Disease 2019 (COVID-19):

Chloroquine or Hydroxychloroquine

Zahra Sahraei Pharm. D, BCPS , Minoosh Shabani MD ,

Shervin Shokouhi MD, MPH , Ali Saffaei Pharm. D

PII: S0924-8579(20)30095-9
DOI: https://doi.org/10.1016/j.ijantimicag.2020.105945
Reference: ANTAGE 105945

To appear in: International Journal of Antimicrobial Agents

Please cite this article as: Zahra Sahraei Pharm. D, BCPS , Minoosh Shabani MD ,
Shervin Shokouhi MD, MPH , Ali Saffaei Pharm. D , Aminoquinolines Against Coronavirus Dis-
ease 2019 (COVID-19): Chloroquine or Hydroxychloroquine, International Journal of Antimicrobial
Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105945

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© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
1 Aminoquinolines Against Coronavirus Disease 2019 (COVID-19):

2 Chloroquine or Hydroxychloroquine

3 Corresponding Author:

4 Dr. Ali Saffaei

5 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of

6 Medical Sciences, Niyayesh Highway, Valiasr St, Tehran, Iran.

7 Postal Code: 1991953381

8 Telephone: +982188873704

9 Email: alisaffaei.ss@gmail.com

10

11 1. Zahra Sahraei, Pharm. D, BCPS

12 Department of Clinical Pharmacy, School of Pharmacy and Pharmaceutical Sciences

13 Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email:

14 Zahra.sahraei@yahoo.com

15

16 2. Minoosh Shabani, MD

17 Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of

18 Medical Sciences, Tehran, Iran. Email: meinoosh53@yahoo.com

19

20 3. Shervin Shokouhi, MD, MPH

21 Department of Infectious Diseases & Tropical Medicine, Loghman Hakim Hospital, Shahid

22 Beheshti University of Medical Sciences, Tehran, Iran. Email: sh.shokouhi@sbmu.ac.ir

23 4. Ali Saffaei, Pharm. D

24 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of

25 Medical Sciences, Tehran, Iran. Email: alisaffaei.ss@gmail.com

26

27 Dear Sir,

28 Coronavirus disease 2019 (COVID-19) continues to spread rapidly across China. As of

29 March 7, 2020, the infection was reported from 97 countries globally. To date, 103,882

30 patients have been confirmed to have COVID-19, and 3,522 of them have died [1]. Recently,

31 many trials have been designed to determine an effective therapeutic regimen for COVID-19.

32 Of the target regimens, chloroquine therapy is also being considered [2]. Few clinical trials in

33 China have shown chloroquine phosphate, an aminoquinoline used in malaria treatment, to be

34 effective against COVID-19 at a dose of 500 mg/d [3]. Chloroquine phosphate also played a

35 promising role in the management of the Zika virus and SARS virus outbreaks. Chloroquine

36 acts by increasing the pH of intracellular vacuoles and altering protein degradation pathways

37 through acidic hydrolases in the lysosomes, macromolecule synthesis in the endosomes, and

38 post-translational protein modification in the Golgi apparatus. In macrophages and other

39 antigen-presenting cells, chloroquine interferes with the antigen processing, thereby

40 achieving an antirheumatic response [4]. Studies have demonstrated that chloroquine also

41 confers its considerable broad-spectrum antiviral effects via interfering with the fusion

42 process of these viruses by decreasing the pH. Additionally, it alters the glycosylation of the

43 cellular receptors of coronaviruses [5]. Hydroxychloroquine (Figure 1), a less toxic

44 aminoquinoline, has an N-hydroxy-ethyl side chain in place of the N-diethyl group of

45 chloroquine.

46 Figure 1. Chemical structure of hydroxychloroquine (a) and chloroquine (b)

47 This modification makes hydroxychloroquine more soluble than chloroquine. Similar to

48 chloroquine, hydroxychloroquine decreases the pH and confers antiviral effects. In addition,

49 hydroxychloroquine has a modulating effect on activated immune cells, downregulates the

50 expression of Toll-like receptors (TLRs) and TLR-mediated signal transduction, and

51 decreases the production of interleukin-6 [6]. Although the antimalarial activity of

52 hydroxychloroquine is equivalent to that of chloroquine, hydroxychloroquine is preferred

53 over chloroquine for its lower ocular toxicity [7]. Retinopathy is a dose-limiting adverse

54 effect of hydroxychloroquine, but a safe daily dose seems to correspond to 6.5 mg/kg of the

55 ideal body weight and 5.0 mg/kg of the actual body weight [8]. Although there are more

56 clinical data about chloroquine’s anti-coronaviral activity than those about

57 hydroxychloroquine’s, both these agents are theoretically similar in their antiviral activity [9].

58 Moreover, chloroquine is not as widely available as hydroxychloroquine in some countries.

59 In addition, chloroquine is associated with greater adverse effects than hydroxychloroquine.

60 For example, in patients with COVID-19, chloroquine can interact with lopinavir/ritonavir,

61 resulting in prolongation of the QT interval. Hence, it is necessary to consider

62 hydroxychloroquine instead of chloroquine when the latter is not available for treating

63 patients with COVID-19. For example, in Iran, chloroquine availability is limited, and

64 hydroxychloroquine can be recommended instead. Other therapeutic agents for COVID-19,

65 such as antiviral agents (Oseltamivir, Lopinavir/Ritonavir, Ribavirin, etc.), interferons, and

66 intravenous immunoglobulins that do not interfere with hydroxychloroquine, are currently

67 under investigation.

68

69 Funding

70 No funding

71 Competing Interests

72 None

73 Ethical Approval

74 Not required

75
 76 References

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82 efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends.

83 2020.

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90 [6] Plantone D, Koudriavtseva T. Current and Future Use of Chloroquine and

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92 Review. Clin Drug Investig. 2018;38:653-71.

93 [7] Lim H-S, Im J-S, Cho J-Y, Bae K-S, Klein TA, Yeom J-S, et al. Pharmacokinetics of

94 Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria

95 Caused by Plasmodium vivax. Antimicrobial Agents and Chemotherapy. 2009;53:1468-75.

96 [8] Jorge AM, Melles RB, Zhang Y, Lu N, Rai SK, Young LH, et al. Hydroxychloroquine

97 prescription trends and predictors for excess dosing per recent ophthalmology guidelines.

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