Hydroxychloroquine; Why It Might Be Successful and Why It Might Not Be Successful in The Treatment of Covid-19 Pneumonia? Could It Be A Prophylactic Drug?

According to current literature and preliminary data, hydroxychloroquine (HCQ) seems potentially effective in treating patients with Covid-19 pneumonia. The concentrations of the HCQ in the lungs might be well above that of plasma. Most likely, this property of HCQ provides effective drug concentrations. HCQ has a gradual onset of action in the treatment of rheumatic diseases. This could be valid for the treatment of Covid-19 pneumonia. Reduced perfusion, somewhat distorted architecture of lung tissue and edema might reduce HCQ accumulation in pneumonic areas of the lungs in Covid-19 pneumonia. Patients having extensive lung involvement might have less HCQ concentrations in their lungs than that of patients having limited lung involvement. Furthermore, patients having extensive lung involvement might have more viral load than that of limited lung involvement. That’s why HCQ might be more effective in the treatment of mild and moderate Covid-19 pneumonia cases and might not be effective in advanced cases. Using HCQ in Covid-19 prophylaxis seems logical since providing enough accumulation of HCQ in the healthy lungs before the arrival of the SARS-CoV-2 virus, might prevent Covid-19 pneumonia. The purpose of this paper is not to recommend using or not using HCQ for the treatment or for the prophylaxis of Covid-19 pneumonia. The purpose of this paper is only to try to bring a new perspective on the role of HCQ in the treatment or in the prophylaxis of Covid-19 pneumonia. This paper proposes only hypotheses, which need further researches to be confirmed.


Introduction
Even though there is no double blind randomized placebo-controlled studies, according to current literature and preliminary data, mainly composed of cell culture, animal and small-uncontrolled human studies, hydroxychloroquine (HCQ) seems potentially effective in treating patients with Covid-19 pneumonia [1][2][3][4][5] . It is very well known that, in normal conditions, no drug can be approved for the treatment of human-beings based on the evidence originating only from cell cultures, animal studies or uncontrolled small studies with the absence of phase I, II, III drug studies.
Since HCQ is an old drug and repurposed for treatment of Covid-19 disease, phase I studies, maybe, phase II studies might not be necessary in normal conditions. Further more, it is almost impossible to determine an exact drug dosage to clear the virus from the body based on the animal or cell culture studies 3,6,7 . However, since there is an urgent pandemic situation, even in the absence of sufficient scientific evidence, the role of HCQ in the treatment of Covid-19 pneumonia is debated among many experts.
Some experts advocate to use HCQ with some precautions or case by case, some advocate waiting for the results of ongoing HCQ-Covid-19 trials, some find its use potentially harmful 8,9 . On he other hand, in practice, HCQ is commonly used for the treatment of Covid-19 disease worldwide. Its use is recommended in interim guidelines of Turkey 10 and Belgium 11 mostly as the first line treatment of mild and moderate Covid-19 pneumonia cases. It is also recommended as a prophylactic drug for Covid-19 disease in India 12 .

Mechanism of Action and Pharmacokinetics of HCQ
HCQ is believed to shown its antiviral activity against SARS-CoV-2 virus at least by two ways, first by interfering with the glycosylation of ACE2 receptor, thus reducing the ability of the SARS-CoV-2 virus to bind on the ACE2 receptors existing on the surface of the host cells, second increasing the endosomal pH which blocks further stages of viral replication 1-3 . In addition, since HCQ might be a zinc ionophore and zinc might have some antiviral effects 13,14 it might also be hypothesized that addition of zinc to HCQ therapy might be more effective than HCQ alone 15 . However, data about HCQ plus zinc therapy for Covid-19 disease is very limited for now.
Hydroxychloroquine (HCQ) has a large volume of distribution. It is believed that mainly tissue accumulation is responsible for the large volume of distribution of HCQ. Current literature indicates that tissue concentrations of HCQ are well above the plasma concentrations. The concentrations of the HCQ in the lungs might be 200-700 times greater than the plasma concentrations. HCQ accumulates in great amounts in liver, kidneys, lungs and other organs or tissues 2,3,16-18 . Most likely, this property of HCQ provides effective viral inhibiting drug concentrations in tissues 1-3 . In addition, since HCQ is a weak base, it accumulates in acidic compartments in the body mainly in lysosomes and inflamed tissues 1,2,16,19-23 which might constitute the majority of the tissue concentration of the drug that might also enable HCQ to block SARS-CoV-2 virus replication 1-3 . HCQ could be transported into tissues by lymphocytes, leukocytes or monocytes since HCQ can also accumulate in these cells 16,19,24 . The plasma concentrations of HCQ are well below the inhibitory levels of SARS-CoV-2 virus.
The elimination half-life of HCQ is shown to be very long which might mainly be attributed to slow releasing of HCQ from the drug-accumulated tissues into the blood 2, [16][17][18] . It was also shown that the bioavalibity of the HCQ might be variable among patients 18,20,22,23 .

Background of Hypothesis
Currently, HCQ is used mainly for the treatment of rheumatic diseases. In the context of rheumatology, HCQ has a gradual onset of action that is HCQ is a slow acting anti rheumatic drug and, it may take several weeks to show its action however full therapeutic efficacy may be seen after a few to several months of therapy [20][21][22][23] .
Steady state drug levels can be achieved using regular daily HCQ doses after several weeks. This is mainly determined by the complex interaction among absorption, distribution, metabolism and elimination of HCQ. Since HCQ have a large volume of distribution, tissue accumulation might be considered as one of the major determinants of these factors. Thus the delayed effect of HCQ in rheumatic diseases can be mainly attributed to its slow accumulation in the tissues [20][21][22][23] . Gradual onset of action of HCQ could also be valid for Covid-19 pneumonia treatment, thus a considerably long time might be needed for HCQ to achieve therapeutic drug concentrations in lungs, that's why starting HCQ therapy as early as possible seems logical.
Small thrombi, vascular injury, interstitial fibrosis, vascular wall thickening, lumen stenosis and occlusion, diffuse alveolar damage, thickened alveolar capillaries, edema, fibrin thrombi in capillaries and small vessels, and inflammatory cells in diseased areas of the lungs might be seen in Covid-19 pneumonia patients 25,26 .
According to histopathological findings, some pulmonary capillaries and some small vessels seem involved (partially) as wall thickening, fibrin thrombi, thrombi, vascular stenosis and occlusion in Covid-19 pneumonia. These abnormalities might cause poor perfusion of diseased lung areas [25][26][27][28] . Hypoxic pulmonary vasoconstriction might also contribute to reduced pulmonary perfusion 27 . Reduced perfusion, pulmonary edema and somewhat distorted architecture of lung tissue might reduce the drug delivery into these pneumonic areas. Eventually drug concentrations in the pneumonic areas of the lungs might be reduced even though HCQ is prone to accumulate in (acidic) inflamed tissues due to its weak base property [19][20][21][22][23]  pneumonia is usually presented with bilateral scattered ground glass opacities and some consolidations ranging from minimal to extensive involvement of the lungs in chest CT scans [30][31][32][33] . The more advanced the disease might be the more radiologic involvement in covid-19 pneumonia 30

Frequency of Side Effects of HCQ; Is it Really Harmful in the Context of Covid-19 Treatment?
Currently, HCQ is used mainly for the treatment of rheumatic diseases.
Hundreds of thousands of patients or more use HCQ worldwide for these diseases.
Even though HCQ can cause many side effects, retinopathy was consistently Retinopathy is a significant side effect however it might appear after consuming daily