Monday, March 23, 2020

The Coronavirus: Potential Treatments and Drugs to Potentially Avoid

Pharmacology and SARS-CoV-2

I have taught pharmacology, the science of drugs, going on thirty years. Several matters related to pharmacology have appeared regarding SARS-CoV-2. I will address two broad questions. First: do some drugs work against the virus? Second: do some drugs make the infection worse?

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Let's start off with some perspective. All of this is new. Even a quick study rushed to publication takes months: and we are not many months into this infection. There is no definitive statement regarding any of these matters, just a handful of very recent publications along with too many anecdotal reports. In the early days of AIDS (of which I have some familiarity), a lot of the original information about treatment candidates proved to be born out of desperation rather than usefulness.

Coronaviruses, along with rhinoviruses and adenoviruses, are among those that cause the common cold. That's the bad news: common colds are common. They are readily transmissible and, as we all know, there is no cure for the common cold. Beyond that, SARS-CoV-2 is much more dangerous than a typical cold or flu.

On the other hand, treating the SARS-CoV-2 virus is not the same as curing the common cold. We are not targeting all of the potential "cold" viruses here: just one. That provides hope for vaccines, and perhaps, pharmaceutical agents. (Strictly speaking, vaccines are pharmaceutical agents, but for the sake of this piece, I'll only be talking about non-vaccine drugs.) Some of the drugs mentioned here were tested during previous SARS outbreak.

Potential Drugs to Treat Coronavirus

These are some of the drugs that have been put forward as to helping with COV-19 infection.

Oseltamivir (Tamiflu). This drug is taken orally to help curtail influenza disease course. It is useful only if the drug is taken within the first two days of symptoms. Even then, it will only briefly shorten the recovery time. Oseltamivir helps prevent newly-formed viral particles from escaping an infected cell and therefore infecting new cells. It does this by inhibiting the neuraminidase enzyme. It is available orally and that's probably why it is prescribed a lot: convenience. In contrast, zanamivir (Relenza) is an inhalant that also inhibits neuraminidase used for flu. It has less side effects than oseltamivir because it is an inhalant: less gets to the blood, more hangs around the lungs where it is needed. Perhaps the best thing about oseltamivir is that it can be used for prophylaxis of the flu, which is especially helpful in high intensity infection settings such as nursing homes.

I've never been a big fan of oseltamivir. Its window of use is brief, its maximum effect is limited, and its side effects are potentially problematic. When I was hospitalized for bacterial pneumonia I was started on oseltamivir -- six days after arrival. That made no sense to me unless there was a concern I was coming down with a secondary infection. I experienced hallucinations. I can't be sure it was the oseltamivir, but delirium is one of its side effects.

Oseltamivir has not been shown to be effective in the previous SARS outbreak, nor did it change long-term outcomes of previously infected SARS patients. It is unlikely that it will work for the current coronavirus.

Favipiravir (Avigan) is fascinating. It has been shown to have efficacy for a variety of RNA-viruses. It has been approved for use in China, Japan, and Italy and has made it through a pair of Phase 3 studies in the US for the treatment of influenza. (China and Italy approved it just this past week.) Its mechanism of action is similar to that of ribavirin and remdesivir (below): they all inhibit RNA virus RNA polymerase.

On March 17, China announced that they had completed clinical studies for favipiravir and that it was helpful in recovery from the disease. To quote:

"The Third People's Hospital of Shenzhen in Guangdong province conducted a clinical trial on 80 patients, with 35 receiving the drug. The results have shown patients treated with favipiravir took four days before being tested negative, whereas the control group took 11 days."

That's a pretty dramatic difference. It is said to not be helpful in severe disease. As I discussed in my pharmacology class, with severe viral diseases such as influenza, all the cells that are going to be infected are infected.

I am surprised by their description of "no obvious adverse effects," same source as above, however, Phase 2 trials in the US showed a low degree of side effects.

Phase 3 studies against influenza virus were finished in 2015. No results have been presented. That suggests the results were not good, at least against the flu virus. Good results get published and the drug is put in for approval.

Remdesivir is much like favipiravir, only earlier in being studied. It has the same mechanism of action. Studies are beginning now.

Lopinavir/ritonavir (Kaletra in combination). These are anti-HIV protease inhibitors. There is no reason to believe they should work on coronavirus and an initial study indicates that they don't.

Chloroquine (Araclen) and hydroxychloroquine are classical antimalarial drugs. For decades chloroquine was the drug of choice against malaria due to being effective while being safer than the others. Now chloroquine-resistant malaria dominates the world and, we have some newer choices that are more powerful, the artemisinins. Hydroxychloroquine is also an antiinflammatory and is used for rheumatoid arthritis.

When I said these are safer than other antimalarials, I didn't mean that they don't have any toxicities. Like quinine, chloroquine and hydroxychloroquine can affect blood sugar. It can cause headaches, diarrhea, and hemolytic anemia in patients with G-6-PD deficiency.

There has been one smallish study that found that azithromycin (an antibacterial protein synthesis inhibitor, Zithromax) and hydroxychloroquine helped to dramatically reduce the length the patient carried the virus and the amount of the virus. The drop out rate was high (6 out of 26) among those initially treated with three of those going to the ICU and one dying. All in all, the study is open for interpretation as either hopeful or problematic. As is usually the case, more studies are needed.

Another study from China found efficacy from chloroquine and remdesivir, in vitro. 

So how does chloroquine or hydroxychloroquine help? That's unknown. Perhaps it is the anti-inflammatory effect. The azithromycin might be preventing secondary bacterial pneumonia infection or it might be due antiviral properties that azithromycin is claimed to have. Furthermore, azithromycin is also an antiinflammatory. On the other hand, since chloroquine has been shown to be effective in vitro, that suggests its effect is more than the antiinflammatory actions.

Concerns about what drugs not to use.

ACE inhibitors / Angiotensin Receptor Blockers (ARBs)

These drugs are standard care for high blood pressure and are used as adjuncts in congestive heart failure. Do they make coronavirus symptoms worse? There are three reasons why this is suspected.

1) SARS-CoV-2 uses the angiotensin coverting enzyme type-2 as a cell receptor for infection.
2) ACE inhibitors, in particular, have been shown to upregulate angiotensin converting enzyme. 
3) Among the co-morbidities for death in Italy in one study, 74% of patients had high blood pressure. This might simply be because high blood pressure and age have a strong association. Age also presents a strong association with SARS-CoV-2 lethality.

In a recent commentary, it was strongly suggested that patients do not stop using these popular blood pressure medicines: the evidence for bad outcome with SARS-CoV-2 infection is not clear. The authors disclosed pharmaceutical ties. Nevertheless, the advice is generally sound.

Ibuprofen / NSAIDs / Acetaminophen.

Ibuprofen in particular was mentioned as something that might be avoided. The director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci, suggests that this is an alarmist extrapolation from aspirin in viral infections causing Reyes' syndrome in children. Others have suggested that fever has a place in the body's fight against infections, and that NSAIDs and acetaminophen lower fever.

Let's take these one by one. The Reyes' concerns should not carry over to other NSAIDs and should not affect decisions in adults. For children, for pain and fever, it is generally recommended to avoid aspirin. Some physicians recommend acetaminophen. Acetaminophen overdose is so common, I would go with a non-aspirin NSAID.

Is lowering the fever in the case of a viral infection a bad strategy? Is the body fighting the infection with fever? In the case of bacterial infections this makes more sense to me. When culturing human pathogenic bacteria, the classic temperature of the heating device is 98.6 F (37 C). This concept to  doesn't pass over to viruses. Viruses in the blood are not going to affected by a fever. Viruses perform their main functions, including replication inside of cells, which I suspect are less susceptible to overall body temperature changes. That said, there is an argument that the induction of heat-shock proteins is protective. In the cited study, the temperature was raised to 40 C (104 F), which is a fairly heavy duty fever, the upper range below emergency.

Asthmatics are advised to avoid NSAIDs. This is because NSAIDs block the production of prostaglandins and the action of blocking the production of prostaglandins shunts the precursors over to leukotrienes, some of which mediate inflammation, and, in particular, mediate inflammation in asthma. If those leukotrienes are exacerbating symptoms in coronavirus patients with compromised respiration, this may be a concern. Of course, some asthma patients will have coronavirus. Perhaps using a leukotriene synthesis blocker such as zileuton could be helpful to overcome this.

The FDA is stating that there is not enough evidence to exclude the use of NSAIDS in coronavirus.

So, what's the bottom line? This is my take. If you have mild symptoms of fever and aches and you don't know if you have coronavirus, and you are over 12 years of age and don't have asthma, take an aspirin or other NSAID. The most significant exception to that rule is if you are allergic to aspirin. In the same situation if you're under 12, then try acetaminophen or ibuprofen. If you have coronavirus and you are not actively have problems breathing, then the NSAIDs are okay. For asthma, acetaminophen will not cause the problems with peripheral leukotrienes.

NSAIDs may be contraindicated if the infection is severe and with active respiratory problems. Even then, the evidence is out.

My primary sources in putting this together were (a) Anthony Fauci's March 18 podcast with the editor of the Journal of the American Medical Association, and (b) Derek Lowe's In the Pipeline blog as part of Science Translational Medicine, his March 6th and (c) March 19th entries.



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