Sunday, March 29, 2020

Coronavirus | Can drugs for Ebola be used to treat COVID-19?

What are the medicines being considered for the novel coronavirus pandemic?

The story so far: Globally unknown till under 200-days ago, the virus SARS-CoV-2, has today, according to the World Health Organization (WHO), caused the world’s largest pandemic. Over half-a-million people are under lockdown, over six lakh are infected and nearly 29,000 dead globally. In India, the numbers stand at a shade below 1,000 cases and 24 deaths (as on March 28, 9 p.m.). The number of cases is growing despite the unprecedented measures put in place by the Central and State governments. With the rise in cases, India has now joined the world in the search for drugs to treat COVID-19. Earlier this week, India approved the use of the anti-malarial drug, hydroxychloroquine, as a preventive medication for people at high risk, such as health workers and immediate contacts of a person who has tested positive for COVID-19.


What is causing death in COVID-19 patients?

In India, COVID-19 deaths have been seen in mostly the elderly population with other health issues including diabetes. Emerging data from China and Italy show that COVID-19 patients have severe blood-clotting disorders that lead to respiratory failure and death. Vaccination has been ruled out as an immediate solution, with WHO noting that even if the process is fast-tracked, a vaccine would take over 18 months to be ready for use. The discovery and licensed use of a drug comes with a long-gestation period.

Hence, WHO and other health agencies are re-looking the efficacy of known therapies and drugs this time to treat COVID-19.

Dr. Raman R. Gangakhedkar, Head of Epidemiology and Communicable diseases at the Indian Council of Medical Research (ICMR), said India, like the rest of the world, does not have the luxury of time to look for new treatment or vaccines right now, “though five vaccines have gone into animal toxicity tests. Our best bet right now is looking at re-purposed drugs”.

With this in mind, WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, recently announced the launch of ‘Solidarity’, a giant multinational trial for testing therapies that researchers have suggested may be effective against COVID-19.

He said, “It is launched to generate robust, high quality evidence as fast as possible.” India, on Friday, aligned with the study after having so far stayed away due to its small sample size, according to the ICMR. WHO said, “This is now is an all-out, coordinated push to collect robust scientific data from across the world.”


What are the drugs being considered?

WHO is looking at some of what doctors and researchers believe are the most promising therapies including a combination of two HIV drugs, lopinavir and ritonavir (used in India also for an Italian patient in Rajasthan), anti-malaria medications, chloroquine and hydroxychloroquine, and an experimental antiviral compound called remdesivir.

As for hydroxychloroquine, a senior Health Ministry official clarified this by saying: “This drug has been brought in at an experimental level and the general public has been cautioned that it is not for use without a doctor’s prescription. To counter any shortage of the drug supplies we have banned the export of the finished drug and its component ingredients.”

A small study conducted in France found it led to a significant reduction in viral load in COVID-19 patients.


What does the research say so far?

The drug, remdesivir, developed to treat Ebola and related viruses, is being tested to find out whether it can be used on COVID-19 patients. Says WHO in research material it has released: “It works by shutting down the viral replication. This was first tested in a COVID-19 patient diagnosed in the United States, when his condition started worsening, according to a case report in the New England Journal of Medicine. The condition of the patient improved.”

The international health community has maintained that of the drugs in the Solidarity trial, remdesivir has the best potential — the drug shows that it can be used in high doses without causing toxicities.
 

What about anti-malaria drugs?
Chloroquine and hydroxychloroquine are decades-old anti-malarial drugs. Hydroxychloroquine is being looked at in India and the ICMR has said that it is currently studying the drug action in the Indian population with respect to COVID-19. After being left out from the ‘Solidarity trial’ previously, the two drugs were brought back for consideration when some countries showed interest in its potential.

A study on 20 COVID-19 patients in France who were given hydroxychloroquine showed a significant reduced viral load in nasal swabs. Hydroxychloroquine, in particular, is known to have a variety of side-effects, and can in some cases harm the heart. “People with heart conditions are at higher risk of severe COVID-19,” warns cardiologist Dr. Naresh Trehan, who heads Medanta Hospital.

The combination drug, ritonavir/lopinavir, was introduced two decades ago to treat HIV infections. Doctors in Wuhan, China, gave 199 patients two pills of lopinavir/ritonavir twice a day plus standard care, or standard care alone.

There was no significant difference between the groups as per reports submitted on March 15. Says Dr. K.K. Aggarwal, former head of the Indian Medical Association, “Although the drug is generally safe it may interact with drugs usually given to severely ill patients, and doctors have warned it could cause significant liver damage.”

He added that another combination under testing is interferon-beta, which WHO has cautioned might be risky.

Says Dr. Aggarwal, “15% of COVID-19 needs hospitalised care and of these 5% need ICU care. Now with time running out rapidly for the entire world, re-purposed drugs are being aimed at to contain the problem, reducing hospital load, freeing critical hospital beds and allowing people to swiftly return to normal work. Agencies are also looking at unapproved drugs that have performed well in animal studies with the other two deadly coronaviruses, which cause Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).”


Is plasma therapy a possibility?
The world health community is also looking at plasma or antibody therapy for COVID-19 with China using it recently on its patients. WHO had recommended its use against Ebola, and issued protocols for its use to treat MERS but its clear-cut benefit to treat COVID-19 cases is still under investigation.

The novel coronavirus hails from a family on which work has already been done worldwide after SARS and MERS. Says Dr. Gangakhedkar, “This really helps in research in the sense that we don’t have to start from scratch. This is vital in our hunt for drugs to contain this virus.”


Why is the lockdown necessary?
Lav Agarwal, Joint Secretary, Union Health Ministry, says, “The lockdown will give us time delay, maybe push back any surge towards community transmission of COVID-19. It is also helping us to re-draw our strategy to cope with this very strong and infectious virus. India has asked all State governments to be prepared in terms of manpower, hospital facilities and care for patients.”

India is now readying its health infrastructure to cope with a virus that has tested the most resilient health-care systems in the world, bringing them to their knees. According to Prof Balram Bhargava, Director-General, ICMR, “This is a crisis like no other and we will have to work together as a nation and an international community. Globally, the problem is being tackled with great urgency. The way out is to find a sustainable solution quickly.”

Blood Plasma Of Those Who Have Recovered From Covid-19 Could Provide Immunity Cover To Others


An old-school medical procedure that health practitioners today might have only read in the textbooks might provide short-term protection from the novel Covid-19 infection.

The procedure based on the concept of passive immunity — the immunity that is provided when a person is given antibodies to a disease rather than producing them through his or her own immune system — and involves blood plasma.

The plasma is a yellowish liquid component of blood that holds all the different types of blood cells — red, white, antibodies and other components like proteins in a suspension.

Blood plasma is separated from the blood by spinning the blood in a centrifuge with an anticoagulant until the blood cells separate out at the bottom of the tube.

This blood plasma of the people who have recovered from the Covid-19 has antibodies against the particular virus.

The experts first test the plasma to measure the number of antibodies, and then identify donors whose plasma is rich in antibodies.

For the best chances of success, the plasma should contain lots of antibodies, and scientists have to design trials to test it rigorously.

The plasma must be safe and free from not only the novel coronavirus but also other disease-causing agents that might be in the blood of the donor.

After testing, the plasma is administered to those who are sick or have high exposure to the virus, like health-care workers. The antibodies in the plasma boost their immunity against Covid-19.

This is called the convalescent plasma approach. In the past, the approach has been used against polio, measles, mumps, and flu.

Dedicated researchers look for the people whose immune system has an exceptional response to different viruses. Their plasma can be used to provide passive immunity to others, or antibodies can be extracted and used for developing drug therapies.

As part of the drug, these antibodies can be cloned to meet the demand, instead of having to draw out the blood from a recovered person for plasma transfer which would require a large number of donors.

However, while antibody therapies take around a year and a half to be developed, the convalescent plasma approach is a quicker option.

It’s not a long term solution though, like a vaccine or an antiviral drug.

The protection offered by convalescent plasma approach (passive immunization) is immediate, but it usually lasts for only a few weeks or months.

On the other hand, vaccines typically need weeks or months to produce protective immunity, and may require repeated doses, but the immunity lasts longer.

But, while the vaccine and drugs are still in the making, convalescent plasma approach can be used to protect the most vulnerable.

Additionally, the passive immunisation can also compensate for a deficient immune system, as the body doesn’t have to synthesise its own antibodies.

However, those who receive the plasma can also have an adverse reaction to the “foreign” entities entering the body.

There are regulatory, logistical and scientific hurdles in setting up a process for the convalescent plasma approach against the novel coronavirus. And even after that, the process can ultimately only be used to treat a limited number of people.

Nonetheless, the plasma approach can help protest the health workers and others who need to be strategically protected for the time being.


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Friday, November 16, 2018

Anti-malaria drugs help in treating cancer

According to previous researches, anti-malaria drugs known as chloroquines were repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor.
 
Now, researchers  explained that an enzyme called PPT1 - opens up a new pathway for potential cancer treatments. 

The team also used CRISPR/Cas9 gene editing to remove PPT1 from cancer cells in the lab and found that eliminating it slows tumor growth. They detailed a potent chloroquine, known as DC661, that can take advantage of this new treatment pathway.

"The discovery of this target is critical because chloroquines are currently being evaluated in clinical trials all over the world, and this knowledge fundamentally changes the way we look at those trials," said the study's co-senior author.

PPT1 is an enzyme which helps in controlling both the mechanistic target of rapamycin (mTOR), a major regulator of growth in cancer cells, as well as a process called autophagy, a built-in resistance mechanism which allows cells to survive when under attack by breaking down unneeded parts and recycling them to stay alive.
In a previous study, researchers showed these two processes work hand-in-hand, as autophagy provides the nutrients that allow mTOR to direct growth, while mTOR shuts off autophagy when the nutrients aren't needed.

Building off their previous work, researchers used CRISPR/Cas9 to knockout PPT1 from cancer cells to see if its removal had the same effect as a chloroquine.

Researchers further proved that the concept by targeting melanoma cells with DC661, which specifically targets PPT1 and produces cell death in many cell lines tested both in vitro and in vivo. It is a dimeric form of the antimalarial drug quinacrine - meaning it has two molecules of quinacrine bound together with a special linker.
The researcher added that when you put the pieces together, it shows incredible promise.

"We now have a specific molecular target in cancer, as well as a potent way to reach it," he said. "It not only provides a new context for current clinical trials involving hydroxychloroquine but also, with further development of these compounds toward clinical drug candidates, it opens the door for head-to-head testing of our compounds or their optimized derivatives versus current chloroquines to see which is more effective." 

 

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Saturday, April 19, 2014

Innovative method to fight malaria

An anti-malarial treatment that lost its status as the leading weapon against the deadly disease could be given a new lease of life, with new research indicating it simply needs to be administered differently.
The findings could revive the use of the cheap anti-malarial drug chloroquine in treating and preventing the mosquito-borne disease, which claims the lives of more than half a million people each year around the world, DECCAN Chronicle reported.
The parasite that causes malaria has developed resistance to chloroquine, but research carried out at the Australian National University (ANU) and Germany's University of Heidelberg has shown that the parasite protein that causes resistance has an Achilles' heel. 
"We studied diverse versions of this protein and in all cases found that it is limited in its capacity to remove the drug from the parasite," said malaria researcher Dr Rowena Martin.
"This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day," said Martin. Once hailed as a wonder drug, chloroquine is still used in developing nations in the South Pacific, Africa, Asia and South America , but has been withdrawn from use in many developed countries. 
Martin and her colleagues also revealed how the protein may have developed resistance to chloroquine. "We found that the protein gains the ability to move chloroquine out of the parasite through one of two evolutionary pathways, but that this process is rigid one wrong turn and the protein is rendered useless," she said. 
"This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies," said Martin. Martin said the findings could be used to help millions of people in developing nations who are at risk of catching malaria.
She said that there is also potential to apply the findings to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.

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