Hi All,
I have found a few articles which explore the subject of whether any existing drugs and in particular any of the tki s used in CML treatment could have been repurposed to have treated the SARS outbreak of 2003 and the MERS outbreak of more recent times.The pathogens that are apparently responsible for these two previous outbreaks are cousins of Covid 19 being in the same family of corona viruses.
There are two reasons for such studies being undertaken;the first is an attempt to understand better the mechanism of infection and the host proteins that viral replication relies on and secondly the need to find existing approved drugs and compounds that might be repurposed to treat the current epidemic .The latter is in the context of any new drug would need to be developed in vitro (in the glass/dish in the lab) before being tested on living organisms such as mice or people-the process including trials could take at least ten years so the possibility of using existing drugs off label or for another condition or purpose is tempting to explore.So my question is might existing tkis be used as antivirals to prevent infection or alleviate symptoms once infected with a corona virus?
In their efforts to understand the mechanism of infection by the corona virus researchers have found that ABl1 and ABl 2 proteins play a significant role in the replication of the virus and depend on a host protein to to survive .It was found that in the case of SARS and MERS that Imatinib "inhibits the virion fusion between the corona virus and endosomal membranes" It was found Abl 2 is more important for replication than ABl 1-apparently in mammals there are 2 ABl kinases.
In the research studies Imatinib came out at the top of the list of existing drugs and compounds gleaned from drug libraries with Dasatinib the other kinase signalling inhibitor being less effective (because of the possible immuno suppressive effect of the drug);nilotinib seemed to be effective for only one of the corona virus pathogens.Imatinib in other studies seemed to block the progress of the Ebola virus and some other unusual poxviruses.
As we know the over activation of the ABl1 pathway can lead to CML but it seems that the corona viruses depend on the ABl2 pathway for their replication but whether imatinib is able to inhibit ABl 2 in the same way as it does for ABl1 is a major query for me.It was found that a dose of imatinib 5 hours before the virus infection started to take hold was 50 times more effective than 5 hours afterwards.Some authors conclude that on existing evidence imatinib might help those going in to highly infected areas or for those greatest at risk of receiving a heavy viral load eg frontline medical staff.
Apparently the imatinib dose used in the experiments was high but I could not find out how high .There is the issue of now undertaking studies in vivo on mice or humans and whether the results are promising or not.The half life of imatinib is 18 hours and for some substrates of it 40 hours ,so if we take our pills every day we always have a level of the drug in us but would this be enough to give us some form of protection and does Covid 19 behave in the same way as the others in the family SARS and MERS?
I came across a small study with a limited sample undertaken very recently in Wuhan that looked at the performance and outcomes of CML patients that developed Covid 19;it concluded that those with co morbidities ,age over 70, men and those not in full molecular remission fared worse.However it was not looking at whether CML patients are less likely to contract the COVID19 virus and especially those currently being dosed with imatinib.
Please stay safe.
Regards
John
