After the outbreak of COVID-19 pandemic, the pressure increased in the research world to find an appropriate drug against the viral infection. Some researchers brought light to a previously used drug hydroxychloroquine, which is mainly used against antimalarial and autoimmune diseases.

Since there are no currently approved drugs for COVID-19, as we know some are on its tried. In the view of recent studies on chloroquine and hydroxychloroquine (HCQ) a research article was published in the journal “DIABETES AND METABOLIC SYNDROME: CLINICAL RESEARCH AND REVIEWS” in which the researchers aimed to review the existing literature about these drugs and COVID-19, and adverse effects related to this drug.

They collated all the available evidence that has emerged so far on the efficacy of chloroquine and hydroxychloroquine, in the treatment of patients with COVID-19, with or without diabetes and present a perspective on both these compounds. Additionally, they have also gathered the currently on-going trials with both these compounds against the COVID-19. 

Studies of chloroquine and hydroxychloroquine conducted in vitro:

WHAT IS CHLOROQUINE (CQ)?

Chloroquine is an antimalarial drug and also can inhibit microorganism inside the cell include coronaviruses and it can do it by various methods some are, Chloroquine increases endosomal pH and interferes with the glycosylation of cellular receptor of SARS-CoV and thereby it has the potential to block viral infection and also 

chloroquine also inhibits the enzyme quinone reductase-2, which is involved in sialic acid synthesis and this is required for recognition of ligand which will modify the process further inside the cells and makes this a broad antiviral agent.                                                                                                                                              It is important to note that both human coronavirus HCoV-O43 and orthomyxoviruses (family of       single-stranded RNA viruses) uses sialic acid moieties as a receptor.

HOW CQ TACKLE CORONAVIRUS INSIDE THE CELL ?

Chloroquine changes the pH of lysosomes and likely inhibits cathepsins, which activates at lower pH and they cleave proteins that lead to the formation of the autophagosome which cleaves SARS-CoV-2 spike protein. Spike protein is one of the major structural proteins of severe acute respiratory syndrome-coronvirus. It is essential for the interaction of the virions with host cell receptors and subsequent fusion of the viral envelop with the host cell membrane to allow infection. And the scientist used this method to inhibit the fusion of the viral and the host cell and then infection of the coronavirus will not occur.     

HOW CQ INHIBIT IN LATE ENDOSOME AND HELP IN CHANGE THE pH INSIDE THE CELL.
: Involvement of the endocytic pathway and autophagy in the entry and replication of CoVs in host cells.

Entry of CoVs into the host cells is mainly done by the endocytic pathway, meanwhile the autophagy has also been implicated in the viral replication in the cells, a process partly related to the formation of DMV in the host cells. As a result, several groups of inhibitors including the lysosomotropic agents mean a drug have the ability to  penetrate the lysosomes of particular types of cells such as CQ and inhibitors for clathrin-mediated endocytosis which have a role in shaping rounded vesicles in the cytoplasm for intracellular signaling such as chlorpromazine have been proposed to have therapeutic efficacy against CoVs-induced diseases including COVID-19.

Furthermore, chloroquine through the inhibition of MAP-kinase (a cell signal mechanism) interferes with SARS-CoV-2 molecular crosstalk, besides altering the virion assembly, budding and interfering with the proteolytic processing of the M proteins is a virulence factor covered in protein and sugar help them in entry into the host cell. So by interfering with the assembly the virus will not replicate properly inside the host cell and then not able to infect another cell.

it is believed that chloroquine can also interfere with ACE2 receptor glycosylation (It plays a critical role in determining protein structure, function and stability) thus prevents SARS-CoV-2 attachment to the target cells (ACE2 receptors recognize the virus and promote its entry into host cell). 

So hydroxychloroquine is a good antiviral due to its favorable penetration in tissues including the lung. Both chloroquine and hydroxychloroquine act as a weak base that can change the pH of acidic intracellular organelles including endosomes/lysosomes, essential for the membrane fusion and if membrane doesn’t fuse with lysosomes the phagolysosome lowers the pH to break down the stuff inside of itself. It is believed that both the agents could be effective tools against SARS-CoV-1 and SARS-CoV-2

CQ METHODS TO INHIBIT COVID-19
Flow chart on how CQ will protect from corona virus infection

HYDROXYCHLOROQUINE

       Some data show HCQ effectively inhibited both 

  • the entry of virus in the host cell
  • transport of viral particles in assembly and 
  • the post-entry stages of SARS-CoV-2, 

similar to the chloroquine and one study found HCQ to be a stronger medicine than chloroquine in inhibiting SARS-CoV-2 in vitro.

Addition of hydroxyl molecule makes HCQ difficult passed through to blood-retinal the barrier consists of cells that are joined tightly together to prevent certain substances from entering the tissue of the retina. and allows faster clearance from retinal cell, thereby suggesting a lesser risk of retinal toxicity with HCQ, as compared to chloroquine and can give a disease called Retinopathy is any damage to the retina of eye it was associated with greater age and with greater accumulative doses of chloroquine. Thus, hydroxychloroquine can be used safely with minimal risk of toxicity.

Furthermore, the narrow therapeutic and safety index margin with chloroquine makes HCQ a safer option than chloroquine.                          

TI VALUE IN SAFETY INDEX

       TI = LD50/ED50  

  • Where the ED50 is the effective (therapeutic) dose in 50% of people                                                             
  • the LD50 is the lethal dose in 50% of people. 
  • Remember: The closer the TI is to 1, the greater the chances of adverse effects. 
  • Drugs that have a low TI have a narrow margin of safety.

The Long-term clinical safety profile of HCQ is better than that of chloroquine, that allows a higher daily dose of HCQ with less drug-drug interactions.

 And there are some other drugs also like Remdesivir is a nucleoside analog treatment with this improve the condition of the patient and this drug in phase III clinical trials against SARS-COV-2 was launched in Wuhan. This is an experimental drug and cannot available to large scale population and therefore scientist use the potential drugs CQ and its derivative HCQ, found to be effective and cheaper in cost.

DIFFERENCE BETWEEN CQ, HCQ AND REMDESIVIR

table 1

Chloroquine and hydroxychloroquine effect on human COVID-19

Moreover, The National Health Commission of the People’s Republic of China recommended inclusion of chloroquine in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19. 

DOSE: In this study, chloroquine was given in a dose of 500 mg of chloroquine twice daily in mild to severe COVID-19 pneumonia

Hydroxychloroquine alone and combination of HCQ plus azithromycin was highly and significantly effective in clearing viral nasopharyngeal carriage in only three-to six days in COVID-19 subjects, compared to control.

These results of converting a potential carrier to a seronegative patient is of importance with regards to preventing community transmission of COVID-19. 

Since the data from Wuhan, China showed that some patients were a carrier as long as up to 37 days (usually around 20 days), results of this study are very encouraging in the context of converting a patient to the seronegative subject within 6 days.

A Central Clinical Task Force from Korea who have treated 27 cases of COVID-19 recommend using lopinavir 400mg/Ritonavir 100 mg BID or Chloroquine 500 mg orally per day or Hydroxychloroquine   400 mg orally per day for 7 to 10 days, in moderate to a severe case of COVID-19

The only viral disease where chloroquine was modestly effective so far before COVID-19 era was chronic hepatitis C suggesting an increased virological response.

What caution you should we take from CQ and HCQ?

 Expectedly, some precautions will be needed while using both these drugs that include frequent monitoring of hematological parameters (RBC, WBC and platelet counts), measurement of serum electrolytes, blood glucose (because of lower glucose the level potential of HCQ) and hepatic as well as renal functions Since both these drugs have the potential to prolong QTc, routine electrocardiography is essential before starting these drugs.       

What drug you should not take with CQ or HCQ?

Giving this CQ and HCQ with other drugs known to prolong the QTc interval (such as anti-arrhythmic, anti-depressants, anti-psychotics, antihistaminic, teneligliptin, ondansetron and moxifloxacin etc.) must be avoided.

  • Additional use of azithromycin with HCQ is done by scientists and this may increase the chances of QTc prolongation. Therefore it should be mandatory to do ECG daily if QTc is anything greater than or equal to 0.50 sec is consider to be dangerous for any age and for any gender.
  • Additionally, hypoglycemia must be looked for in patients with diabetes especially with simultaneous use of chloroquine/HCQ and lopinavir/ritonavir. Chloroquine and HCQ should not be used simultaneously with lopinavir/ritonavir and remdisivir for expected QTc prolongation. 
  • Finally, pharmacovigilance which plays a role in healthcare through evaluating and discovery of interactions amongst drugs and their effects in human and visual and mental disturbance are also closely required.

All clinicians using these drugs must know caution to both these compounds and not give this CQ and HCQ to patients who have the following problems:

  • Hypersensitivity to these agents,                                                                                                                      
  • Retinopathy:  is any damage to the retina of the eyes, which may cause vision impairment.                                                                                                                                                               
  • Porphyria :  Disorders resulting from the build-up of certain chemicals related to red blood cell proteins.                                                                                                                                                                         
  • Epilepsy: neurological disorder in which brain activity becomes abnormal, causing seizures or periods of unusual behavior .                                                                                                                                                                    
  • Pre-existing maculopathy: is when the macula is a part of the eye and the most sensitive spot sustains some form of damage. One such cause of macular damage from diabetic macular.                                                                                                                                          
  • G6PD deficiency: A condition causing red blood cells to break down in response to certain medications, infections, or other stresses.                                                                                                                                                                                                                      
  • Recent myocardial infarction and                                                                                                                                             
  • QTc >500 msec.                          
  • Chloroquine is not contraindicated in pregnancy.

HCQ can be used as a supplement to control glycemia in adult patients with type 2 diabetes (approved for treatment in India). However thr role of such supplementary treatment for testing its potential role as a prophylaxis (action is taken to prevent disease) of COVID-19 in diabetes, has not been researched but could be attempted (in view of above) considering higher mortality in patients with diabetes, as compared to non-diabetic subjects with COVID-19

WHEN SHOULD BE REGULARLY CHECK IF YOU ARE TAKING CQ OR HCQ
Flow chart on what should be regularly check when you are administrated with CQ or HCQ daily

Conclusion 

  • Considering minimal risk upon use
  • Cost-effectiveness and easy availability across India, 
  • Scientist proposes that both these drugs are worthy of fast track clinical trial for treatment
  • Since HCQ has been approved for treatment of diabetes in India, it should be further researched in diabetes and COVID-19, a subgroup where significant mortality has been shown.

Meanings

  • Glycosylation is the process by which a carbohydrate is covalently attached to a target macromolecule, typically proteins and lipids. This modification serves various functions. For instance, some proteins do not fold correctly unless they are glycosylated.
  • Cathepsins (kata- “down” and hepsein “boil”; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes.
    • Autophagy acts as a maintenance apparatus that is designed to keep the cell functioning properly by removing, or rather recycling waste.
    • The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. An abnormally long or abnormally short QT interval is associated with an increased risk of developing abnormal heart rhythms and sudden cardiac death

    REFERENCE:

    Singh, A.K., Singh, A., Shaikh, A., Singh, R. and Misra, A., 2020. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: a systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews.

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