Journal of Cardiology Research Reviews & Reports

Introduction
Coronavirus

Human coronaviruses (HCoVs) were first reported in 1965 by Tyrrell and Bynoe, and it was named as B814 [1]. Coronaviruses are the largest RNA viruses, enveloped, single-stranded, and belongs to the family Coronaviridae in the order Nidovirales [2,3]. They are widely distributed among birds, mammals, and humans [2,4,5]. There are six species of coronavirus that cause human illness. 229E, OC43, NL63, and HKU1 are typically associated with common cold symptoms [6]. The other two species are originally zoonotic and included sever acute respiratory syndrome (SARECoV) which was the related pathogen for SARE-CoV in Guangdong Province, the republican of China in 2002 and 2003, causes severe lung disorder, leading in some cases to systemic infection and eventually death in about 10% of cases and the middle east respiratory syndrome coronavirus (MERS-CoV) that was the causative agent for MERS-CoV disease in the middle east which was first reported in Saudi Arabia in 2012 [4,7-11].

On December 31, 2019, several patients in Wuhan, China started reporting symptoms that resembled pneumonia [12]. A new virus was identified and initially called the 2019 novel coronavirus (2019-nCoV) [13]. On January 30, 2020, the World Health Organization (WHO) named the disease as “COVID-19” which is coronavirus disease 2019 [14]. Although the COVID-19 started in december 2019 in Wuhan, China, soon it spreads worldwide and on march 11, 2020, the who officially described the COVID-19 outbreak as a pandemic [15].

Chloroquine

Quinines have been in medical use against malaria for over 350 years. The source of these materials is the bark of the Cinchona trees [16,17]. Chloroquine is a 4-aminoquinoline derivative of quinine that was originally synthesized by Hans Andersag in 1934 when he was working for Bayer in Germany through the condensation of 4-7-dichloroquinoline with 1-diethylamino-4- aminopentane [18].

CQ eliminated very slowly from the body, remaining in significant concentrations for several days or even weeks. [19,20]. If it is taken in proper doses, CQ is an extraordinarily safe drug [17,21]. Retinal toxicity has been described with long-term use (years) of CQ and HCQ and may be related to over-dosage of these medications [22-24] which can be avoided by taking the daily therapeutic dose [17].

Gastrointestinal upset has been reported with HCQ intake [25]. Besides, CQ is a safe drug if given to infants and pregnant women [20,26-28]. The synthetic form hydroxychloroquine (HCQ) was introduced in 1955 and differs from chloroquine only by a hydroxyl group which decreases its toxicity, increasing its solubility, while conserving its efficacy [18,29- 32].

Chloroquine, the antimalarial drug, elicit antiviral effects against several viruses. This antiviral activity could be by a direct antiviral effect by its concentration in the cell organelles or by indirect effect through its immunomodulatory activity, suppressing the production and release of tumor necrosis factor-alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases [5,33,34]. CQ proved to be effective against several viruses including Dengue Virus [35], hepatitis B virus herpes simplex virus type 1 human immunodeficiency virus type 1[34,36-40].

It has been shown that CQ uptake by the lung tissues is much more than others such as brain, heart, kidney, skeletal muscle, adipose tissue and liver [41]. Moreover, pretreatment with chloroquine increased the organotropic accumulation of particles designed to target the lungs [42]. Which makes it effective in preventing or treating pulmonary COVID-19.

In 2003, Savarino and colleagues hypothesized that CQ might be of some use for the clinical management of SARS [34]. Previous in vitro studies reported that chloroquine is effective in inhibiting the replication of human coronaviruses (HCoVs) such as SARS-CoV, MERS-CoV, and HCoV-OC43 [2,33,43,44]. Furthermore, in 2009, and in vivo study showed that CQ is highly effective against HCoV-OC43 infection in newborn mice and they suggested that CQ may be considered as a future drug against HCoVs [2].

The most recent studies (2020) reported that CQ is highly effective in the control of 2019-nCoV infection in vitro and also been found that HCQ is effective in inhibiting SARSCoV-2 infection in vitro [45,46]. It was found that HCQ is more potent than CQ at inhibiting SARS-CoV-2 in vitro [47]. Furthermore, an in vivo study, demonstrated that CQ has a strong antiviral activity against HCoV-OC43. Moreover, treatment with daily doses of CQ has a long-lasting protective effect against lethal coronavirus OC43 infection in newborn mice [2].

Therapeutic Dosage of CQ and HCQ

In the early days of the COVID-19 outbreak in China, CQ and HCQ have been used. It was found that HCQ is more effective in treating these patients and its dose was 400 mg/ day for five days [48]. The Italian scientist treated COVID-19 patients by HCQ in a dose of 800 mg as a loading dose followed by 400 mg daily for 10 days. Or 1000 mg CQ daily for 10 days [49]. While the French scientist, to treat their COVID-19 patients, they used HCQ in a dose of 200mg three times a day for ten days and depending on the clinical condition of the patients, azithromycin may be added to the treatment [50].

Nigella sativa

Nigella sativa (Ranunculaceae) commonly known as the Black cumin, Kalonji, black seed or Habbatul Barakah. The use of Nigella sativa (NS) seeds and oil in traditional remedies goes back more than 2000 years, and the herb was described as ‘the Melanthion’ by Hippocrates and Doiscroides [51,52]. Prophet Mohammed (Peace Be Upon Him), more than 1400 years ago, described the curative powers of the black seed as “Hold on to use this black seed, as it has a remedy for every illness except death” [53]. Avicenna, a well-known physician of the 10th century described NS in his book “Canon of Medicine”, has recommended the use of NS seeds for dyspnea, enhancement of body’s energy and also support during recovery from fatigue and dispiritedness [54]. NS is also mentioned for its curative property in the Holy Bible [55,56].

It has been considered as one of the most treasured nutrientrich herbs in history around the world and numerous scientific studies are in progress to validate the traditionally claimed uses of NS seeds and oil [57-61].

NS has been used for the prevention and treatment of various diseases. The main active constituent of NS is thymoquinone which has a very antioxidant action. It is very effective against various illness such as diabetes, hypertension, cancer, inflammation, fever, asthma, pain (headache and back pain), infections (bacterial, viral, fungal, and parasitic), eczema, and many other disorders. For references [52,56,61,62].

Combination of NS with different agents

We and others have shown that the adjunct use of NS seeds, oil or its derivatives with different conventional chemotherapeutic agents will reduce their side effects such as hepatic or renal toxicity [63-67]. Furthermore, the coadministration of NS with other drugs might potentiate and improve the therapeutic index [63,68]. This synergistic action of NS or its derivatives might result in reducing the dosage of concomitantly used drugs [56].

In 2014 Emeka and colleagues reported that the use of NS seed and oil extract as dietary supplements in combination with chloroquine (CQ) has potential in enhancing the efficacy of CQ and could be of benefit in the management of malaria [59]. According to this valuable variety of the medicinal uses of NS, we highly support the previous words describing it as the miraculous plant and considered by earliest herbal specialists as “The herb from heaven” [62].

Therapeutic dose of NS

250-500 mg of NS seeds orally (3.5-5 mg/kg/day), and 0.5-1.0 ml/day NS oil capsules. It is more acceptable to be given with honey [69-71].

Conclusion

COVID-19 is spreading across the world at an alarming rate, threatening the lives of millions of people, especially the elderly and immunocompromised patients. Such huge numbers of infected and dead people call for an urgent demand for effective, available, and affordable drugs to control the COVID-19 pandemic. With proper therapeutic and preventive measures, the disease can be contained and the population protected.

We are suggesting the use of NS as an adjuvant therapy with HCQ to potentiate the effect of HCQ against COVID-19 infection and to reduce any possible adverse effects of HCQ. Furthermore, HCQ with or without NS could be used as a prophylactic measure against COVID-19 infection. The following justify giving a single dose of HCQ or CQ (alone or in combination with NS oil) as a prophylactic measure against CoVID-19 infection:

1. Chloroquine eliminated very slowly from the body, remaining in significant concentrations for several days or even weeks.
2. It is concentrated in the lung more than other body organs.
3. It has antiviral activity in general and anticoronaviruses in specific.
4. Until today CQ and HCQ are used for prophylaxis and treatment of malaria.
5. Both HCQ and NS extracts have very well-known antiviral activities.
6. NS improves the therapeutic index of HCQ.
7. CQ or HCQ are cheap and most available drugs.

The suggested prophylactic dose of HCQ is 200mg of HCQ once only as a preventive measure against COVID -19 disease. While the therapeutic doses of HCQ in the combination of NS have been mentioned above for the treatment of COVID-19 patients.

Conflict of Interest

The authors declare no conflict of interest.

Authors Contributions

Al-Noaemi MC developed the research conception and took the initiatives of this work and drafted the manuscript. Hammoudi AM contributed to collecting, extracting, and organizing the data also revising the review paper and agreed to be accountable for all aspects of the work.

References

1. Tyrrell DAJ, Bynoe ML (1965) Cultivation of a novel type of common cold virus in organ culture. Br. Med. J 1:1467.
2. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, et al. (2009) Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice. Antimicrobial Agents and Chemotherapy53: 3416-3421.
3. Zhu N, Zhang D, Wang W, Li X, Yang B, et al. (2020) A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382:727-33.
4. Zhong NS, Zheng BJ, Li YM, Poon LL, Xie ZH, et al. (2003) Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February 2003. The Lancet 362:1353-8.
5. Cui J, Li F, Shi ZL (2019) Origin and evolution of pathogenic coronaviruses. Nature Reviews Microbiology17:181-92.
6. Su S, Wong G, Shi W, Liu J, Lai AC, et al. (2016) Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends in microbiology24: 490-502.
7. Drosten C, Gü;nther S, Preiser W, Van Der Werf S, Brodt HR, Becker S, et al. (2003) Identification of a novel coronavirus in patients with the severe acute respiratory syndrome. New England journal of medicine 348:1967- 76.
8. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, et al. (2003) A novel coronavirus associated with the severe acute respiratory syndrome. N. Engl. J 348:1953- 1966.
9. Cyranoski D (2003) “China joins investigation of mystery pneumonia”. Nature 422:459.
10. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, et al. (2013) “Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study”. The Lancet Infectious Diseases13: 752-61.
11. Zumla A, Hui DS, Perlman S (2015) Middle East Respiratory Syndrome. Lancet 386: 995-1007.
12. Zhu N, Zhang D, Wang W, Li X, Yang B, et al. (2020) A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382:727-33.
13. Ramphul K, Mejias SG (2020) Coronavirus Disease: A Review of a New Threat to Public Health. Cureus. 12: e7276.
14. WHO Director-General announced “COVID-19” as the name of this new disease on 11 February 2020.
15. Tedros Adhanom Ghebreyesus, Director-General of the WHO announces that the COVID-19 outbreak is a pandemic. March 11, 2020.
16. Mates M, Nesher G, Zevin S (2007) Quinines-past and present. Harefuah 146: 560-562.
17. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y (2012) Hydroxychloroquine: From Malaria to Autoimmunity. Clinical Reviews in Allergy and Immunology 42: 145- 153.
18. Andersag H, Breitner S, Jung H (1941) March. Quinoline compound and process of making the same. US Patent. 1941 2: 233-970.
19. Walker O, Dawodu AH, Adeyokunnu AA, Salako LA, Alvan G (1983) Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria. Br J Clin Pharmac16:701-705.
20. Arrow KJ, Panosian C, Gelband H (2004) Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. Chapter 9. “Antimalarial Drugs and Drug Resistance”. National Academies Press ISBN-10: 0-309- 09218-3.
21. Padberg S (2015) Anti-infective Agents. (Chapter 6). Drugs during Pregnancy and Lactation. Treatment Options and Risk Assessment 115-176.
22. Mavrikakis M, Papazoglou S, Sfikakis PP, Vaiopoulos G, Rougas K (1996) Retinal toxicity in long term hydroxychloroquine treatment. Annals of the rheumatic diseases 55:187-189.
23. Easterbrook M (1993) October. The ocular safety of hydroxychloroquine. In Seminars in arthritis and rheumatism 23: 62-67.
24. Browning DJ (2002) Hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity. American journal of ophthalmology133: 649-656.
25. Srinivasa A, Tosounidou S, Gordon C (2017) Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue? The Journal of rheumatology 44: 398-398.
26. Parke AL, Rothfield NF (1996) Antimalarial Drugs in Pregnancy--The North American Experience 5: S67-9.
27. Abarientos C, Sperber K, Shapiro DL, Aronow WS, Chao CP, et al. (2011) Hydroxychloroquine in Systemic Lupus Erythematosus and Rheumatoid Arthritis and Its Safety in Pregnancy. Expert Opin Drug Saf 10: 705-14.
28. Johnson BA (2012) Prevention of Malaria in Travelers. Am Fam Physician 85: 973-977.
29. McChesney EW (1983) Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J MeD 75: 11-18.
30. Abdulaziz N, Shah AR, McCune WJ (2018) Hydroxychloroquine: Balancing the Need to Maintain Therapeutic Levels With Ocular Safety: An Update. Curr Opin Rheumatol 30: 249-255.
31. Frie K, Gbinigie K (2020) Chloroquine and Hydroxychloroquine: Current evidence for their effectiveness in treating COVID-19. Oxford COVID-19 Evidence Service Team. Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences. University of Oxford.
32. Yao X, Ye F, Zhang M, Cui C, Huang B, et al. (2020) In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases https://doi. org/10.1093/cid/ciaa237.
33. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (2004) In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem. Biophys. Res. Commun 323: 264-268.
34. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (2003) Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect 3:722-727.
35. Farias KJS, Machado PRL, Muniz JAPC, DA Fonseca BAL (2015) Antiviral activity of Chloroquine against dengue virus Type 2 Replication in Aotus Monkeys. Viral Immunol 28: 161-169.
36. Kouroumalis EA, Koskinas J (1986) Treatment of chronic active hepatitis B (CAH B) with chloroquine: a preliminary report. Ann. Acad. Med. Singapore15:149-152.
37. Singh AK, Sidhu GS, Friedman RM, Maheshwari RK (1996) Mechanism of enhancement of the antiviral action of interferon against herpes simplex virus-1 by chloroquine. J. Interferon Cytokine Res 16: 725-731.
38. Pardridge WM, Yang J, Diagne A (1998) Chloroquine inhibits HIV-1 replication in human peripheral blood lymphocytes. Immunol. Lett 64: 45-47.
39. Savarino A, Gennero L, Sperber K, Boelaert JR (2001) The antiHIV-1 activity of chloroquine. J. Clin. Virol 20:131-135.
40. Tsai WP, Nara PL, Kung HF, Oroszlan S (1990) Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res. Hum. Retrovir 6: 481-489.
41. Daniel WA, Bickel MH, Honegger UE (1995) The Contribution of Lysosomal Trapping in the Uptake of Desipramine and Chloroquine by Different Tissues. Pharmacol Toxicol 77: 402-6.
42. Wolfram J, Nizzero S, Liu H, Li F, Zhang G, et al. (2017) A chloroquine-induced macrophage-preconditioning strategy for improved nano delivery. Sci Rep 7:137-38.
43. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, et al. (2005) Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology 2: 69.
44. De Wilde AH, Jochmans D, Posthuma CC, ZevenhovenDobbe JC, Nieuwkoop S, et al. (2014) Screening of an FDA-approved compound library identifies four smallmolecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 58: 4875- 4884.
45. Wang M, Cao R, Zhang L, Yang X, Liu J, et al. (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 30: 269-271.
46. Liu J, Cao R, Xu M, Wang X, Zhang H, et al. (2020) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 6:16.
47. Yao X, Ye F, Zhang M, Cui C, Huang B, et al. (2020) In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). Clinical Infectious Diseases. https://academic. oup.com/cid/advance-article-abstract/doi/10.1093/cid/ ciaa237/5801998.
48. Chen Z, Hu J, Zhang Z, Jiang S, Han S, et al. (2020) Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. doi: https://doi.org/10.1101/2020.03.22.20040758.
49. Nicastri E, Petrosillo N, Ippolito G, D’Offizi G, Marchioni L, et al. (2020) National Institute for the Infectious Diseases “L. Spallanzani” IRCCS. Recommendations for COVID-19 Clinical Management. Infectious Disease Reports 12.
50. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents105949.
51. Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S (2015) Thymoquinone and its therapeutic potentials. Pharmacol Res 95-96:138-58.
52. Tavakkoli A, Mahdian V, Razavi BM, Hosseinzadeh H (2017) Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone. J Pharmacopuncture 20: 179-193.
53. Al-Bukhari MI (1976) In: The collection of authentic sayings of Prophet Mohammad (peace be upon him), division 71 on medicine. 2nd ed. Al-Bukhari Sahi., editor. Ankara: Hilal Yayinlari.
54. Avicenna (1999) Canon of Medicine. Chicago: Kazi Publications.
55. Tariq T (2008) “Nigella sativa seeds: folklore treatment in modern day medicine,” Saudi Journal of Gastroenterology 14: 105-106.
56. Yimer EM, Tuem KB, Karim A, Rehman NU, Anwar F (2019) Nigella sativa L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses. EvidenceBased Complementary and Alternative Medicine https:// doi.org/10.1155/2019/1528635.
57. Takruri HRH, Dameh MAF (1998) “Study of the nutritional value of black cumin seeds (Nigella sativa L),” Journal of the Science of Food and Agriculture 76: 404-410.
58. 59. Ramadan MF (2007) “Nutritional value, functional properties and nutraceutical applications of black cumin (Nigella sativa L.): an overview,” International Journal of Food Science & Technology 42: 1208-1218.
59. Emeka PM, Badger- Badger LI, Eneh CM, KhanTM (2014) Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei. Pharmacogn Mag 10: S357-S362.
60. Hassanien Minar MM, Abdel-Razek Adel G, Rudzi?ska Magdalena, Siger Aleksander, Ratusz Katarzyna, et al. (2014) “Phytochemical contents and oxidative stability of oils from non-traditional sources”. European Journal of Lipid Science and Technology 116:1563-1571.
61. Molla S, Md Abul Kalam Azad M, Md Ali Azam Al Hasib, M Monayem Hossain, Md Sohel Ahammed, et al. A review of the antiviral effects of nigella sativa. PharmacologyOnLine. Newsletter 2:47-53.
62. Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, et al. (2013) A review on the therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 3: 337-352.
63. Badary OA, Nagi MN, Al- Shabanah OA, Al- Sawaf HA, Al- Sohaibani MO, et al. (1997) Thymoquinone Ameliorates the Nephrotoxicity Induced by Cisplatin in Rodents and Potentiates Its Antitumor Activity. Can J Physiol Pharmacol 75: 1356-61.
64. Al-Kubaisy K, Al-Noaemi M (2006) A protective role of Nigella sativa oil against the harmful effect of CCl4 on the liver cells. The Internet Journal of Nutrition and Wellness 3.
65. Essawy AE, AMA, Khayyat LI, Elzergy AA (2012) Nigella sativa seeds protect against hepatotoxicity and dyslipidemia induced by carbon tetrachloride in mice. Journal of Applied Pharmaceutical Science 2: 021-025.
66. Farooqui Z, Shahid F, Khan AA, Khan F (2017) Oral administration of Nigella sativa oil and thymoquinone attenuates long term cisplatin treatment induced toxicity and oxidative damage in rat kidney. Biomed Pharmacother 96: 912-923.
67. Elshama SS (2018) The preventive and curative role of Nigella sativa in poisoning cases. J Clin Exp Tox 2:18-24.
68. Ozugurlu F, Sahin S, Idiz N, Akyol O, Ilhan A, et al. (2005) The effect of Nigella sativa oil against experimental allergic encephalomyelitis via nitric oxide and other oxidative stress parameters. Cell Mol Biol (Noisy-legrand) 51: 337-42.
69. Ansari MA, Ahmed SP, Haider S, Ansari N (2006) Nigella sativa: A non-conventional herbal option for the management of seasonal allergic rhinitis. Pak J Pharmacol 23: 31-35.
70. osiawan TI, Linda W, Etty W (2012) Anti-Malaria Study of Nigella sativa L. Seed Water Extract in Mus musculus Mice Balb C Strain In Vivo. Makara Journal of Science 16: 192-196.
71. Gholamnezhad Z, Shakeri F, Saadat S, Ghorani V, Boskabady MH (2019) Clinical and experimental effects of Nigella sativa and its constituents on respiratory and allergic disorders. Avicenna journal of phytomedicine 9:195.