Take-at-home COVID drug molnupiravir may be on its way — but vaccination is still our first line of defence

Nial Wheate, University of SydneyThe Australian government has pre-purchased 300,000 courses of an experimental antiviral oral drug called molnupiravir.

Interim results announced by the company, US pharmaceutical Merck, show the drug halved the number of patients who ended up in hospital due to COVID. No patient who took the drug died from the virus.

But the drug isn’t yet available for dispensing from pharmacies because it hasn’t received approval from Australia’s drug regulator, the Therapeutic Goods Administration (TGA).

If approved it can be used in the community to prevent patients with mild symptoms from developing more severe disease.

Until then, there will be no legal, effective and safe treatments that people with COVID can take at home to keep them out of hospital. As such, we need to continue our push to get maximum vaccination coverage within the community.

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What is molnupiravir?

Molnupiravir is an experimental antiviral drug that acts against a range of respiratory viruses, including the virus that causes COVID.

For COVID, the instructions for creating more virus are contained in the virus’ RNA. This RNA needs to be read and copied to make new virus particles.

Molnupiravir works by disrupting the replication of the virus. It does this by mimicking two natural compounds called cytidine and uridine that are needed to make RNA. When the body tries to replicate the virus it incorporates molnupiravir into the RNA structure instead of versions of cytidine and uridine. The result is the accumulation of mutations in the virus RNA which then prevent it from causing illness.

This type of technology isn’t new. In fact, we have been using chemotherapy drugs that mimic RNA and DNA ingredients for over 50 years. One drug, called fluorouracil works by preventing DNA production inside cancer cells by mimicking the DNA ingredient thymine.

Results of the clinical trial

Last week Merck announced interim results of a phase 3 clinical trial of molnupiravir.

The company found the drug significantly reduced the risk of hospitalisation or death in patients who took the drug when compared with patients who took a placebo treatment. In fact, the results were so good, an independent data monitoring committee recommended the trial be stopped early.

Overall, the drug reduced hospitalisations and deaths by around 50%. While 14.1% of patients who took placebo ended up in hospital, only 7.3% of molnupiravir patients had the same outcome.

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What is sotrovimab, the COVID drug the government has bought before being approved for use in Australia?

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The results were even better with regard to the death rates. No patient who took molnupiravir died, while eight patients in the placebo group did die.

Importantly, while the clinical trial demonstrated efficacy of the drug, it was also able to show molnupiravir is safe. The rate of side effects was nearly the same in both the molnupiravir and placebo groups. Earlier clinical trials found there are no serious side effects with the drug. The most common, mild effects were headache and diarrhea.

We have to wait for the full data to be released and checked in order to be fully confident in the drug. But the results seem to indicate molnupiravir may be useful for the early treatment of COVID to prevent the development of serious disease and hospitalisation.

How it will be used

Molnupiravir will be able to be taken orally by patients at home after they receive a prescription from their doctor.

A course of treatment will be eight 200 milligram capsules a day for five days; four capsules in the morning and four capsules in the afternoon. A patient can choose whether they want to take the medicine with or without food, as it doesn’t appear to affect the medicine in the body.

It’s unclear whether a positive COVID test will be required before a prescription can be issued. This is something that will be decided by the TGA.

Health Minister Greg Hunt said he encourages Merck to apply for registration of the drug, and the TGA has stated it’s willing to receive an application for provisional registration at which time they can evaluate the data themselves.

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Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Coronavirus Treatment

Got a child with COVID at home? Here’s how to look after them

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Brendan McMullan, UNSW and Philip Britton, University of SydneyThe Delta variant is more infectious and is leading to more COVID-19 cases in children than previous strains.

Many parents are wondering whether Delta is making kids sicker, and how to care for their children if they get COVID.

It can be a nerve-racking time for parents, but there are practical things you can do to make your child more comfortable if they’re ill.

How common is COVID in kids, and how sick do they get?

There have been more than 50,000 confirmed COVID cases in Australia.

Of these, 4,625 cases have been in children aged 0-9, and 6,325 among those aged 10-19 — totalling approximately 20% of all Australian cases.

Symptoms in children are often like those of other viral infections and may include fever, runny nose, sore throat, cough, vomiting, diarrhoea and lethargy.

A small number of children have other symptoms such as tummy pains, chest pain, headache, body aches, breathing difficulties or loss of taste or smell. Up to half of children with COVID may be asymptomatic.

Despite evidence the more-infectious Delta variant is causing more severe illness in young adults, there’s no convincing evidence it has caused more severe illness in children to date.

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Most children can be cared for at home. Hospital networks, including children’s hospitals and local networks, are helping parents and carers to support this care at home.

In some cases, children and families may be transferred to special health accommodation to provide safe isolation and care.

How can I best care for my child at home if they get COVID?

Caring for a child with COVID will look similar to the general supportive care for children with other viral infections.

Children should be dressed in appropriate clothing, so they’re comfortable — not sweating or shivering.

Parents and carers should make sure the child drinks lots of fluids. They can also take paracetamol or ibuprofen if they are uncomfortable with pain or fever. These medicines should be administered as directed in the product information or by a health professional.

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Warning signs of deterioration include prolonged fever (for more than five days), difficulty breathing or chest pain.

Some children get severe abdominal pain, vomiting and/or diarrhoea. It’s important to encourage these children to frequently drink fluids. It’s a concern if they’re drinking less or passing urine less than half of what they normally would, or if they are excessively sleepy or irritable.

For these or other serious concerns, parents and carers should seek urgent advice from their care team. In an emergency, they should request ambulance assistance, informing the operator the child has COVID.

Don’t some children end up in hospital or intensive care?

Yes, there’s a small risk of severe disease from COVID in children but this is very uncommon, even in children who have medical vulnerabilities.

Children and adolescents can develop inflammatory complications after COVID, though this is rare. Symptoms include persistent fever and rash, among others. These conditions, termed “Multisystem Inflammatory Syndrome in Children (MIS-C)” or “Paediatric Multisystem Inflammatory Syndrome (PIMS-TS)” have been reported mainly in the United States and Europe.

Estimates from the US suggest these occur in around one in 3,000-4,000 cases of COVID in children. There’s only been a handful of cases reported in Australia to date.

Children aged 12-15 in Australia are now eligible for vaccination, and vaccination trials are ongoing for younger children.

Do children get ‘long COVID’?

There has been increasing concern about prolonged symptoms after COVID infection, sometimes called long COVID, even with mild disease.

Fortunately, this is rare in children. In a study of more than 150 children with mild or asymptomatic COVID in Australia, most symptoms resolved in 4-8 weeks and children generally returned to their baseline health within 3-6 months.

What if some people in the home aren’t infected?

The SARS-CoV-2 virus spreads easily from one person to another, particularly in close contact and for those living in the same household as someone who has the virus.

You can reduce the risk of spread by:

• keeping more than 1.5m distance where possible
• getting the child to use a separate bathroom, if this is available
• wearing a mask (for adolescents and older children); younger children and others who cannot wear a mask can be encouraged to observe the other behaviours
• covering coughs and sneezes
• performing regular hand hygiene with soap and water or hand sanitiser.

Good ventilation is also a factor in reducing transmission, but not everyone can modify this in their living situation.

If someone in the household has COVID, high touch surfaces such as door handles, kitchen bench tops, switches and taps should be regularly cleaned.

Personal household items such as cutlery, dishes and towels should be washed before being shared. Regular household disinfectant is sufficient.

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The authors would like to acknowledge Christine Lau, paediatrician, and Nadine Shaw, clinical nurse consultant, Sydney Children’s Hospitals Network, for their contributions to this article.

Brendan McMullan, Conjoint Senior Lecturer, School of Women’s and Children’s Health, UNSW and Philip Britton, Senior lecturer, Child and Adolescent Health, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

What is sotrovimab, the COVID drug the government has bought before being approved for use in Australia?

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Elise Schubert, University of Sydney; Lifeng Kang, University of Sydney, and Nial Wheate, University of SydneyAustralia currently has drugs that treat the symptoms of COVID, and drugs which have been repurposed from other diseases. Now the government has placed an early order for a new drug, sotrovimab, which works on COVID-19 virus particles in the body.

The federal government has bought 7,700 doses of sotrovimab (pronounced so-tro-ve-mab), with an initial delivery due some time this year.

But the COVID-19 Clinical Evidence Taskforce says the clinical trial results are too preliminary for the drug to enter routine use here. The taskforce says until further evidence shows sotrovimab is effective, it should only be given to patients as part of a human clinical trial.

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What type of drug is it?

Sotrovimab is a newly developed monoclonal antibody-based medicine. This means it stops the action of the virus that causes COVID-19.

Antibodies are a type of protein in the immune system. Antibodies can recognise and attach to another type of protein called an antigen.

When an antibody attaches to the antigen, it triggers a series of reactions, which can be used to treat an associated disease.

Monoclonal antibody drugs are used for other conditions.
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Monoclonal antibody drugs are already established in modern medicine and are used to treat diseases such as arthritis and cancer.

Another monoclonal antibody drug called tocilizumab is used to treat some of the inflammatory symptoms associated with COVID-19.

How does sotrovimab treat COVID?

Sotrovimab works by binding to the spike protein on the outside of the COVID-19 virus. This is the same spike protein the body’s immune system is trained to recognise with the Pfizer COVID vaccine.

By binding to the spike protein, sotrovimab can block the virus from attaching to and entering human cells. This stops the virus replicating in the body.

How is sotrovimab given and what are the side effects?

The US Food and Drug Administration has approved sotrovimab for emergency use as an intravenous injection to treat COVID-19 patients at high risk of progressing to severe disease.

Sotrovimab can be given as soon as someone receives a positive test result or within ten days of getting COVID-19 symptoms.

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The most common side effects with sotrovimab are rash and diarrhoea. Patients also need to be closely monitored for severe allergic reactions after the injection.

What have clinical trials shown so far?

In May 2021, pharmaceutical company GlaxoSmithKline released data from a clinical trial. It compared sotrovimab to a placebo in 583 at-risk COVID-19 patients to see whether it prevented the disease progressing to the extent that the patient needed to be hospitalised or died.

In the sotrovimab group (of 291 people), three patients saw their disease progress, compared to 21 in the placebo group (of 292 people). This amounts to an 85% reduction of disease progression in patients with mild to moderate COVID-19.

Has it been approved by medical regulators?

In May, both the US and European drug regulators authorised sotrovimab to be used in adults and children aged over 12 with mild to moderate COVID-19, but who are at a high risk of progression to severe COVID-19. This includes people aged over 65, and those with certain medical conditions such as heart disease, obesity, asthma, and diabetes.

Australia’s regulator, the Therapeutic Goods Administration (TGA), has received an application from GlaxoSmithKline to provisionally register the drug here in Australia, however its use remains limited to research settings.

So far, sotrovimab can only be used in research settings in Australia.
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So what does that mean for Australia?

Yesterday federal health minister Greg Hunt announced the government had purchased 7,700 dose of sotrovimab, based on the recommendation of its Science and Industry Technical Advisory Group.

The intention is to have the drug ready for use once approved by the TGA.

But the COVID-19 Clinical Evidence Taskforce, which creates clinical guidelines for the treatment of people with COVID-19 in Australia, has concerns about “the impact of sotrovimab on patient-relevant outcomes in the treatment of COVID-19” and the potential harms of unproven treatment.

It says sotrovimab should not be used outside randomised human clinical trials that have the appropriate ethical approval:

Trials are needed in special populations, including children and adolescents, pregnant and breastfeeding women, older people living with frailty and those receiving palliative care. Until further evidence is available, do not use sotrovimab for the treatment of COVID-19 in these populations unless they are eligible to be enrolled in trials.

As such, sotrovimab can only enter mainstream use in Australia when the full results of the phase 3 clinical trials are known. That data will be important for the TGA to determine whether the drug works, and whether it’s better than the current treatments.

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Elise Schubert, Pharmacist and PhD Candidate, University of Sydney; Lifeng Kang, Senior Lecturer, University of Sydney, and Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

To ensure supply of the top 3 drugs used to treat COVID-19, it’s time to boost domestic medicine manufacturing

Nial Wheate, University of Sydney; Elise Schubert, University of Sydney, and Ingrid Gelissen, University of SydneyWe now know enough about how COVID works for health authorities to have issued clear guidance on which drugs doctors should use on hospitalised patients. The recommended drugs are dexamethasone, remdesivir, and tocilizumab.

Remdesivir, also known as Veklury, is not manufactured in Australia and the Therapeutic Goods Administration (TGA) has recently issued an alert warning of a shortage of tocilizumab in Australia. And the large dexamethasone manufacturers are based overseas. The website Pharmaoffer, which shows suppliers of active pharmaceutical ingredients, lists the countries that produce the active ingredient in dexamethasone; Australia is not one of them.

More broadly, Australia lacks medicines manufacturing capability and this puts us at significant risk should supplies from overseas continue to be interrupted.

One report released last year described the Australian market for pharmaceuticals as “possibly one of the most vulnerable in the OECD”.

It’s time for Australia to re-invest in domestic medicine manufacturing.

Drugs used to treat COVID-19

Many people diagnosed with COVID-19 experience only mild, or no symptoms at all, and can be managed and monitored at home. Rest is the main treatment, and medicines such as paracetamol and/or ibuprofen can provide symptomatic relief of any mild fevers.

People with moderate to severe COVID-19 are treated in hospital. The medicines doctors will prescribe in hospital depend on a patient’s clinical circumstances, such as whether or not they are receiving oxygen therapy.

The pharmaceutical treatment options include:

• dexamethasone, a corticosteriod
• remdesivir, an antiviral and
• tocilizumab, a monoclonal antibody and immunosuppressive agent (monoclonal antibodies are lab-made proteins that mimic the immune system’s virus-fighting abilities).

Dexamethasone is already used for a wide range of conditions, such as certain forms of cancer and arthritis, and various other disorders. Now, it is used in treatment of COVID-19 to suppress inflammation and immune responses.

Remdesivir works by stopping the replication of viral RNA.

And tocilizumab is sometimes used when COVID-19 patients have signs of systemic inflammation.

Dexamethasone is already used for a wide range of conditions.
Nati Harnik/AP

Where are they made?

Australia is heavily reliant on supply agreements for medicines that come from overseas (and a manufacturing network might include a lot of countries). It’s been reported some of the large dexamethasone manufacturers are in Brazil and India.

To meet growing demand for remdesivir, its company (Gilead) has approved new deals for manufacturing in Egypt, India, and Pakistan. But while the remdesivir manufacturing network now includes more than 40 companies in North America, Europe, and Asia, the medicine is not manufactured in Australia.

Tocilizumab was developed in Japan and is now also licensed for manufacturing by the California-based company Genentech.

Need for Australian manufacturing base

There is an urgent need for Australia to increase local manufacturing of many types of medicines, not just COVID treatments, to secure current and future needs.

In general, Australia does have some medicine manufacturing sites in Australia but several have either closed or are slated for closure.

The Australian government has acknowledged the importance of boosting local production of medicines but it’s unclear what progress has been made.

In March this year, an interim report by the Productivity Commission on vulnerable supply chains again indicated medicines as an area of concern, noting that

the pharmaceutical industry is highly regulated, making entering the market or modifying existing facilities to respond to a crisis a slow and costly process.

The final report from this committee is currently with the government.

Manufacturing of medicines in Australia is regulated by the TGA. According to its website, it can take up to 12 months for an Australian manufacturer to get approval to bring a new manufacturing site online. This means it would take us a long time to act if a supply shortage pops up.

Significant backing from the federal government for local medicine manufacturing would reduce the risk of key medicine shortages in Australia, while also creating many highly skilled jobs.

Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of Sydney; Elise Schubert, Pharmacist and PhD Candidate, University of Sydney, and Ingrid Gelissen, Associate Professor in Pharmaceutical Sciences, School of Pharmacy, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Cardiac arrests in young people — what causes them and can they be prevented or treated? A heart expert explains

Wolfgang Rattay/AP/AAP

Jessica Orchard, University of SydneyOn June 12, 16,000 spectators at Copenhagen’s Parken Stadium and millions of viewers around the world watched in shock as Danish midfielder Christian Eriksen’s heart stopped.

Late in the first half of Denmark’s opening game of the Euro 2020 soccer tournament against Finland, the 29 year-old was running just after a throw-in and suddenly collapsed. It appears he suffered a sudden cardiac arrest.

Fortunately, he was quickly attended to by a medical team with full resuscitation equipment, who administered CPR and successfully used a defibrillator. Erikson survived and has been fitted with an implantable cardiac defibrillator. This is a small device which is connected to the heart and fitted under the skin. If a dangerously abnormal rhythm is detected, it will deliver an electric shock to the heart to try to restore a normal rhythm.

So how often do cardiac arrests happen in young people? What are the risk factors, and can they be prevented?

Cardiac arrests during sport are extremely rare. If you’re playing sport next weekend, you should go ahead in the knowledge it’s almost certain not to happen. The benefits of exercise far outweigh the risks.

But because events like this do happen, albeit very rarely, we need public venues to have good emergency plans to improve survival, including the widespread availability of defibrillators.

There have been some recent improvements in this regard in Australia. For example, defibrillators are now installed in all Coles and Woolworths stores nationally, and there are several programs to support rollout of defibrillators and emergency action plans to community sports clubs. But there’s still room for improvement.

Am I at risk? How often does this happen?

Sudden death from cardiac arrest in a young person is a very rare but tragic outcome. The baseline risk in Australia for people under 35 is 1.3 per 100,000 people per year, with 15% occurring either during or immediately after exercise.

Across all ages, there are 20,000 sudden cardiac arrests in Australia that occur out of hospital every year, and sadly only 10% of people survive.

It’s also worth remembering a cardiac arrest isn’t exactly the same thing as a heart attack. A heart attack occurs when one of the coronary arteries is blocked, stopping blood supply to part of the heart. A cardiac arrest is when the heart stops pumping blood around the body, and can occur due to a heart attack or another cause.

The major causes of cardiac arrest depend on age. In people over 35, the vast majority are caused by coronary artery disease, where arteries supplying blood to the heart are blocked or damaged.

In people aged under 35, there’s no single major cause of cardiac arrest. Some of the conditions that can cause cardiac arrest in young people include:

• a condition where the heart muscle becomes too thick, called “hypertrophic cardiomyopathy”
• other conditions of the heart muscle that make it harder for the heart to work properly (called “cardiomyopathies”)
• a condition called “Long QT syndrome” which can cause a dangerously erratic heartbeat
• “Brugada syndrome”, which is a heart rhythm disorder.

However, 40% of sudden cardiac deaths in young people remain unexplained even after autopsy.

Is cardiac screening the answer?

Cardiac screening in young people looks for certain heart abnormalities that haven’t yet been detected. It’s common for elite and professional athletes in Australia and internationally, and is mandatory for young athletes in some countries, for example Italy and Israel.

This screening usually includes a “12-lead electrocardiogram” or ECG, which is a painless test that involves putting some sticky dots on the body and recording the electrical activity of the heart over a ten second period.

However, ECG screening cannot detect all of the conditions which can cause sudden cardiac arrests. This is because some conditions don’t show ECG abnormalities before a cardiac arrest.

Eriksen’s condition was likely in that category, because we know he had regular heart screenings while at Tottenham and these hadn’t shown any problems.

Medicare in Australia funds heart health checks for people who are middle aged or older, but not in younger people. This is similar to most countries. Other than in professional athletes and those with a family history, most professional bodies don’t recommend widespread screening of younger people because the risk of cardiac arrests is so low overall.

How else can we prevent sudden cardiac death? Defibrillators and data

The best strategy for preventing sudden cardiac death at any age is having defibrillators widely available. A defibrillator is a device that can analyse the heart’s rhythm and deliver an electric shock if needed. This can shock the heart back into a normal rhythm.

While they obviously can’t stop the cardiac arrest happening in the first place, they are crucial to survival once they do happen. Early access to a defibrillator can improve survival to almost 90%.

However, access needs to be very quick, ideally within 2-5 minutes, as we know the chances of survival drop by 10% for every minute of delay before defibrillation.

We also need as many as people as possible to be regularly trained to provide CPR.

Fabrice Muamba, a former midfielder for the Bolton Wanderers soccer team in the UK, was lucky to survive after he collapsed and his heart stopped on the field during a 2012 FA cup quarter-final.

Muamba, who recovered after he received CPR and 26 defibrillator shocks, last week voiced his support for defibrillators to be a legal requirement in public places in the UK. Ideally, Australia could also introduce a similar requirement to have defibrillators in public venues, supported by widespread CPR training (including how to use a defibrillator) to improve survival rates from out of hospital cardiac arrests.

In addition to defibrillators and CPR training, venues such as schools and sporting stadiums need to have good cardiac emergency plans so they can respond efficiently and effectively if someone’s heart stops.

Some of the conditions that are diagnosable prior to a cardiac arrest run in families, such as “Long QT syndrome”. So, it’s important to seek medical advice for anyone with a family member who has had cardiac arrest under the age of 40.

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Importantly, anyone who has any worrying symptoms should seek medical advice, especially fainting or collapse during exercise.

Finally, research projects such as the Australian End Unexplained Cardiac Death (EndUCD) registry are urgently needed to identify the underlying causes of cardiac death in young people so we can prevent deaths from sudden cardiac arrest.

Jessica Orchard, Postdoctoral Fellow, Centenary Institute; and Adjunct Senior Lecturer, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Could a simple pill beat COVID-19? Pfizer is giving it a go

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Peter Wark, University of NewcastleWhile the focus has been largely on vaccines, you might have also heard Pfizer is trialling a pill to treat COVID-19.

It almost sounds too good to be true. Indeed, the results are very preliminary — but it’s a promising approach.

Where most antiviral agents we’ve tried to treat COVID-19 target the inflammatory and immune response resulting from infection, Pfizer’s pill directly targets SARS-CoV-2 — the virus itself.

Mounting our defence against the virus

Much of the illness associated with COVID-19 is due to the intense inflammatory and immune response that can occur with an infection. The most successful treatments so far have targeted this overzealous immune response.

Taken early in the disease, the inhaled corticosteroid budesonide has been shown to reduce the development of more severe disease.

In people hospitalised with COVID-19 requiring oxygen, the oral corticosteroid dexamethasone reduces the likelihood of death.

In the most severe cases — COVID patients admitted to ICU — the anti-inflammatory tocilizumab administered intravenously gives a person a better chance of survival.

But these treatments don’t target SARS-CoV-2 itself; just the consequences of infection. Directly targeting the virus has proven to be more difficult.

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Have Australian researchers developed an effective COVID-19 treatment? Potentially, but we need to wait for human trials

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Targeting SARS-CoV-2

A virus like SARS-CoV-2 must enter a host cell to reproduce. It does this using its spike protein (a protein on the virus’ surface) to attach to the cell, and then it uses the cell’s own proteins to gain entry.

Once inside the cell, SARS-CoV-2 removes its outer coat and releases its viral RNA (ribonucleic acid, a type of genetic material). This acts as a template, allowing the virus to replicate, and then infect other cells. At any point of this life cycle the virus could be vulnerable to an intervention.

SARS-CoV-2 carries an enzyme, 3C-like protease (3CLpro), which plays a crucial role in the replication process. This protease is almost identical to the protease used by the SARS-CoV-1 (SARS) virus, and similar to the protease used by the Middle Eastern Respiratory Virus (MERS).

So a drug that could effectively target 3CLpro and prevent virus replication could be beneficial against multiple known coronaviruses, and possibly any that emerge in the future.

SARS-CoV-2 uses its spike protein to attatch to a host cell.
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Protease inhibitors have been successfully used to treat other viral infections, especially chronic infections such as HIV and hepatitis C.

They were put forward early in the pandemic as a possible treatment for COVID-19. But the HIV drug lopinavir-ritonavir was shown in two clinical trials to be ineffective, with drug levels probably too low to work against SARS-CoV-2. While a higher dose might be effective, it would also likely produce more side effects.

Scientists also proposed a repurposed antiviral drug, remdesevir, originally developed to treat Ebola. Remdesivir delays the ability of the virus to replicate its RNA.

Initial case reports appeared promising and saw the US Food and Drugs Administration approve the drug for emergency use. But the results of randomised controlled trials in hospitalised patients with severe COVID-19 were disappointing.

Although there was a reduction in duration of illness for patients who survived, it didn’t significantly reduce a person’s chance of dying.

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Of course, neither of these agents were designed specifically to target SARS-CoV-2. But in 2020, Pfizer/BioNtech identified a small molecule — PF-00835231 — that blocks the SARS-CoV-2 3CLpro protease. It was originally designed against SARS-CoV-1, but the enzyme in the two viruses is almost identical.

PF-00835231, both alone and in conjunction with remdesevir, appears to reduce the replication of a range of coronaviruses including SARS-CoV-2 in cells in the lab. It also reduced viral replication in a number of animal models, with no adverse safety signals. But it’s important to note this research hasn’t yet been peer reviewed.

What now?

Pfizer/BioNtech are taking two drugs to clinical trials for COVID-19: PF-07304814, an intravenous injection for use in patients hospitalised with severe COVID-19 and PF-07321332, an oral agent, or pill, that could potentially be used earlier in the disease. Both are formulations of a 3CLpro inhibitor.

These phase 1 trials, which began in March, represent the earliest stage of drug development. These trials select healthy volunteers and use different doses of the drugs to establish their safety. They also look at whether the drugs elicit sufficient responses in the body to indicate they could be effective against SARS-CoV-2.

The next step would be phase 2 or 3 trials to see if they improve outcomes in COVID-19. Usually this process takes years, but as the pandemic continues to rage globally, Pfizer says it will do this in a matter of months, if phase 1 trials are successful.

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The application of antiviral agents in acute COVID-19 has been difficult and unrewarding. Though results are at this stage preliminary, these agents by Pfizer/BioNtech are promising. They could be used early in disease, especially in people poorly protected by vaccination or in those who haven’t been vaccinated.

They could also be used as a means of prevention, to contain outbreaks in exposed people. They should be effective against all the SARS-CoV-2 variants of concern, as well as against other known and possibly emergent coronaviruses.

The Pfizer CEO’s recent suggestion the pill could be available by the end of the year is probably a long shot. But the pandemic has shown us what’s possible in the realm of swift scientific advances, and we’ll watch this space with interest.

Peter Wark, Conjoint Professor, School of Medicine and Public Health, University of Newcastle

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Why the TGA should reschedule MDMA and psilocybin for the treatment of mental illness

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Sarah-Catherine Rodan, University of Sydney and Samuel Banister, University of SydneyThe Therapeutic Goods Administration (TGA) is considering rescheduling psilocybin and MDMA from their current classification as Schedule 9 prohibited substances to Schedule 8 controlled substances.

This would allow psychiatrists to use these drugs in combination with psychotherapy for the treatment of conditions such as depression and post-traumatic stress disorder (PTSD).

Here’s why we believe that would be a good idea.

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A bit of background

On February 3, the TGA announced an interim decision to retain psilocybin and MDMA as Schedule 9 drugs.

The TGA cited limited evidence of therapeutic benefit, safety concerns, potential for abuse, and lack of suitably trained psychiatrists.

But the final ruling, which was expected on April 22, has now been delayed while the TGA seek independent expert advice on the “therapeutic value, risks, and benefits to public health” of the change.

If MDMA and psilocybin are reclassified, they would be administered in a supervised environment.
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The case for MDMA and psilocybin

Research on psychedelic substances such as LSD and psilocybin first began in the 1960s.

The number of clinical trials involving psilocybin or MDMA has increased steadily in the past decade, with more than 70 studies completed since 2010.

Around 60 trials are underway in Europe and the United States involving MDMA or psilocybin.

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The results of completed studies are very promising.

For example, last month, a study of 59 patients with major depression showed just two sessions of psilocybin-assisted therapy was as effective as a six-week course of the antidepressant escitalopram. The proportion of patients who no longer qualified for a major depression diagnosis after treatment was twice as high in the psilocybin group.

This month saw results of one of the largest trials of MDMA-assisted psychotherapy for PTSD published. The phase 3 study used MDMA-assisted psychotherapy to treat 90 patients with severe, chronic PTSD. After three sessions, 67% of participants no longer qualified for a PTSD diagnosis, compared to just 32% of participants undergoing therapy alone.

These latest studies add to a growing number of trials from around the world showing the therapeutic benefit of psilocybin or MDMA in depression, PTSD, anxiety associated with terminal illness, obsessive-compulsive disorder, alcohol and tobacco dependence, and social anxiety in adults with autism.

Scientists are now investigating the use of psilocybin in other conditions for the first time, such as anorexia nervosa, general anxiety disorder, and opioid and cocaine dependence.

Studies are showing MDMA and psilocybin can be effective in treating a variety of mental health problems.
Shutterstock

Are MDMA and psilocybin safe?

Unlike many Schedule 8 medicines, psilocybin- or MDMA-assisted psychotherapy treatments are not taken regularly. The substance is usually used just two or three times with trained specialists as part of a psychotherapy program.

Despite the safety concerns cited by the TGA, there haven’t been any serious adverse reported events due to psilocybin or MDMA from dozens of clinical trials. Less serious effects can include temporary anxiety, paranoia, fear, nausea, post-treatment headaches, or mild increases in blood pressure and heart rate.

Of course, these trials use pharmaceutical-grade drugs administered by a doctor.

However, one of the most comprehensive studies of the harms of commonly used illegal drugs found even illicit forms of psilocybin and MDMA are among the least harmful. In fact, “mushrooms” containing psilocybin had the lowest overall harm score, while illicit forms of clinically-used Schedule 8 substances like cocaine, cannabis and ketamine were all more harmful than psilocybin or MDMA.

We don’t know what dose of psilocybin would be lethal to humans, but it’s estimated to be about 1,000 times greater than the therapeutic dose. No overdose deaths due to psilocybin toxicity alone have ever been reported.

Use of illicitly manufactured MDMA — which often contains other drugs or impurities — has occasionally caused deaths. An estimated 600,000 Australians use illegal MDMA each year, and an average of about three deaths per year since 2000 have been associated with MDMA toxicity alone.

But illicit use of MDMA of unknown dose and purity is much more dangerous than administration of pharmaceutical MDMA under medical supervision in a clinical environment.

A growing field

In recent years, respected academic and medical institutions around the world have launched dedicated centres for psychedelic and MDMA research, including Johns Hopkins University and Imperial College London.

And research into the therapeutic effects of psilocybin and MDMA has recently started in Australia. St Vincent’s Hospital in Melbourne is conducting a clinical trial using psilocybin-assisted psychotherapy to treat anxiety and depression in terminally ill patients. A clinical trial at Monash University is looking at psilocybin-assisted psychotherapy for generalised anxiety disorder and MDMA-assisted psychotherapy for PTSD.

The Australian government recently announced A$15 million in funding for research into the medical potential of psychedelics and MDMA.

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Read more:
Psychedelics to treat mental illness? Australian researchers are giving it a go

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It’s hard to reconcile the TGA’s interim decision to retain Schedule 9 for substances with demonstrated benefit in several mental health conditions and fewer safety concerns than many existing Schedule 8 medicines.

The US medicines regulator recently granted MDMA and psilocybin “breakthrough therapy” designation; a special status for highly promising drugs that speeds up their path to the clinic.

The down-scheduling of psilocybin and MDMA could have enormous medical benefit for Australian patients, especially when Australia spent A$10.6 billion on mental health between 2018-2019.

Sarah-Catherine Rodan, PhD candidate, University of Sydney and Samuel Banister, Team Leader in Medicinal Chemistry, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Have Australian researchers developed an effective COVID-19 treatment? Potentially, but we need to wait for human trials

Nial Wheate, University of SydneyThe world is now 18 months into the COVID-19 pandemic and we’ve yet to find a single drug that can stop the virus. At best, we can treat the effects of the virus through oxygen therapy for those who can’t breathe, and with drugs that reduce the inflammation associated with the infection.

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Dexamethasone: the cheap, old and boring drug that’s a potential coronavirus treatment

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But an Australian-United States research team, led by Griffith University’s Menzies Health Institute, have shown promising results in their mouse trials of a new treatment for COVID-19.

The technology is based on “short interfering RNA”, which prevents the virus from replicating inside human cells. They found a 99.9% drop in the number of virus particles in the mice they studied.

The researchers hypothesise the drug could be injected into patients daily for up to five days, for example for sick patients in hospital, or as a once-off if someone has just been exposed to the coronavirus; however, there’s no data on this specifically, so it’s speculative for now.

While the results are very promising, the technology has only been tested in mice. Human clinical trials will take some time to complete before we know whether a drug will be approved by the government.

 

How viruses work

Viruses are tricky to treat because they are biological molecules made of the same types of materials as the human body. Virus particles are just packets of information on how to make more virus, encoded in a molecule called “ribonucleic acid” or RNA (although some contain DNA instead) within a protein coating.

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Read more:
Explainer: what is RNA?

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Once a virus particle penetrates into a cell, it either hijacks the machinery of the cell to make copies of itself, or in some cases, has its RNA copied into the host cell’s DNA. Either way, the cell becomes a manufacturing facility making hundreds and thousands of copies of the virus.

So the best way to stop a virus is to stop its RNA information being copied and transcribed by the cell.

We already have drugs capable of doing this for specific viruses. A drug called PrEP (pre-exposure prophylaxis) is available as a prophylactic against infection with HIV and the development of AIDS. A prophylactic can prevent a disease before it takes hold in the body.

The PrEP medicine works because the two active ingredients it contains, tenofovir and emtricitabine, block a molecule called reverse transcriptase which the virus needs to be replicated. Unfortunately, neither drug works to block COVID-19.

Short interfering RNA

Unlike PrEP, the new technology is particularly clever because it uses a molecule called short/small interfering RNA or “siRNA” to prevent the reading and copying of the virus information. This siRNA was specifically designed to recognise a sequence of the coronavirus’ own RNA that is common across COVID-variants.

This means the siRNA can seek out and lock onto the viral RNA because it perfectly complements it, regardless of the COVID-19 strain. When it locks with the virus RNA, the viral information becomes trapped and can’t be copied, or it causes the RNA to be cut and degraded.

At this point there is no virus production, and our immune system can just mop up the small number of virus particles floating around the body.

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Read more:
Why are there so many drugs to kill bacteria, but so few to tackle viruses?

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To prove their technology, the researchers enclosed their siRNA in lipid nanoparticles, which are essentially tiny fat-like particles. Without this protective coating, the siRNA would be destroyed in the blood stream before it could lock onto the virus. Lipid nanoparticles are also used in the formulation of the Pfizer and Moderna COVID-19 vaccines.

With the protective nanoparticle shell, the siRNA could then be delivered via a water-based injection into veins.

When the researchers administered the siRNA to mice that had been infected with COVID-19, they found the mice didn’t lose as much weight when compared with untreated mice. Weight loss was an indicator of how sick the mice were.

The researchers also found a 99.9% drop in the number of virus particles in the mice.

On occasion, when biological molecules are injected into the blood stream, this can trigger a severe allergic reaction called anaphylaxis. Importantly, the researchers found their siRNA didn’t trigger an immune response in the mice, and therefore will be unlikely to cause anaphylaxis.

So as well as being effective, the technology appears to be relatively safe.

Will this drug be available soon?

As promising as the results are, we shouldn’t get our hopes up that a drug will be available any time soon. Data derived from animal tests doesn’t always translate to success in humans. Often, the way an animal’s body processes a drug can be different from the human body, and it ends up being ineffective.

Also, animal tests are just the first step in a long regulatory process to prove a drug works and is safe. Even with accelerated clinical trials and fast-tracked assessment from governments, an approved drug is still a year or more away.

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Read more:
Of mice and men: why animal trial results don’t always translate to humans

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Correction: a previous version of this article stated that HIV needed reverse transcriptase to embed the RNA information into human DNA. We’ve amended it to say HIV needs reverse transcriptase to be replicated.

Nial Wheate, Associate Professor of the Sydney Pharmacy School, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

How to treat sunburn pain, according to skin experts

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Katie Lee, The University of Queensland and Monika Janda, The University of Queensland

So you’re one of the 21% of Australians who got sunburnt last weekend.

While we should be avoiding sunburn, it’s sometimes easier said than done in the Australian sun.

What can you do once you realise you’re turning into a temporary lobster?

First, the bad news

Once you’re sunburnt, you can’t undo the damage to your DNA and skin structures, and you can’t speed up skin healing. You can only treat the symptoms.

Sunburn is a radiation burn caused by too much exposure to ultraviolet (UV) rays, causing extensive damage to the DNA in your skin. When your skin’s DNA monitoring and repair system judges there’s too much damage to fix, it flags the cells for destruction and calls in the immune system to finish the job.

The immune cells and extra fluid squeezing into the skin cause the swelling, redness, heat and pain we know as sunburn. Blisters develop when whole sheets of cells die and lift away, and fluid fills in the space below. Later, dry peeling results when large sheets of dead cells peel off to make way for fresh ones.

By the time you get to skin peeling, or ‘desquamation’, your sunburn is almost completely healed.
Rjelves/Wikimedia Commons, CC BY-SA

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Read more:
Explainer: what happens to your skin when you get sunburnt?

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However, while your skin does its thing, you can manage the symptoms and make yourself more comfortable.

Step 1: Prevent further damage and assess your burn

First, get out of the sun until the redness and pain have subsided, even if this takes several days. The full effects of a sunburn can take up to three days to develop, and further UV exposure will only compound the damage.

Next, assess whether to seek medical help. Severe cases can involve second-degree burns, which disrupt the lower layer of skin, the dermis, and stop the skin from regulating fluid loss effectively. If you have a second-degree burn across a large area of you body, complications can include electrolyte imbalances due to large amounts of fluid loss, or shock, also due to extreme fluid loss. Secondary infections are also possible since the upper layer of skin is no longer acting as a tough barrier to germs. You should definitely see a doctor if you:

• have large areas of blistered skin, especially on the face

• have severe swelling

• can’t manage the pain with over-the-counter painkillers

• experience fevers, chills, nausea, dizziness or confusion.

Blistered sunburn in children needs immediate attention from your GP.

Swollen sunburn means you need to see a doctor.
Uddey/Wikimedia Commons, CC BY-SA

Step 2: Ease the suffering

As with a thermal burn, water is your friend. Drink plenty to correct any dehydration from being in the sun too long and replenish the fluid being drawn into your skin. Cool baths, showers or damp cloths ease the sensation of heat and can be used as often as you like throughout the day. Avoid putting ice on a sunburn, as this can make matters worse by causing intense vasoconstriction, where blood vessels narrow sharply and cut off local blood supply to already damaged skin.

Moisturising lotions can also help soothe by keeping moisture in, but avoid skin-numbing creams unless prescribed by your doctor. Any water-based moisturiser should do, including aloe vera gel.

Despite its popularity as a home remedy, there’s surprisingly little research on aloe vera for sunburn specifically. There’s promising data for its use in wound healing, but many studies investigated aloe extracts taken orally, rather than gel on the skin. In any case, a commercial aloe vera gel won’t do you any harm if you find it soothing. However, gel straight from the plant in your garden comes with a risk of soil-borne infections in skin that’s already damaged (warning: gruesome pictures in that link).

Over-the-counter painkillers like ibuprofen or paracetamol can take the sting out of your sunburn and help you rest more comfortably. If your skin is very itchy, try an antihistamine. US guidelines also often suggest low-dose (0.5-1%) hydrocortisone cream; there’s not much evidence for its effectiveness, but it also won’t hurt you to try it for a few days.

If you have blisters, try not to pop them as that exposes the damaged skin underneath to infection; cover them up with a wound dressing if you’re tempted.

While none of these remedies will fix the damage in the way antibiotics fix an infection, they will make you more comfortable while your skin gets on with healing itself.

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Read more:
Monday’s medical myth: we’re not getting enough sun

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Step 3: Make a plan

While you’re stuck inside, pinpoint how you got burnt and how you might prevent it next time. Most sunburn happens when you did not expect to be outdoors for long, or when you thought sunburn was unlikely because the weather was cool, windy or cloudy. UV radiation is still present in these conditions, but you don’t have the benefit of feeling hot to remind you to get out of the sun.

Did you forget to put sunscreen on a section of your body?
Charlie Brewer/Wikimedia Commons, CC BY-SA

Here are a few familiar scenarios:

• got burnt when you unexpectedly had to park 10 minutes’ walk away? Apply sunscreen as part of your daily routine whenever the UV index will be 3 or over. This will protect you from these sneaky sunburns and also from sub-sunburn levels of UV damage. Don’t worry — there’s no evidence wearing sunscreen every day will make you vitamin D deficient or cause a toxic build-up of chemicals in your body

• arrived at the cricket and realised you left your hat or sunscreen at home? Many venues offer free sunscreen, so ask at the check-in or the health and safety officer

• coming in from the beach, garden or bike ride just a bit too late? Sunscreen won’t protect you all day, so make sun-protective clothes part of your regular attire — a rashie, long-sleeved shirt, or UV-protective armguards and leggings

• got to the park BBQ when all the shady spots were taken? Arrange your next outing to avoid the most UV-intense middle of the day. The SunSmart app or Bureau of Meteorology weather report will tell you the UV forecast and when you need sun protection

• forgot to reapply sunscreen? Set an alarm on your phone next time to remind you.

The more you practise this kind of thinking, the easier it will become.

The SunSmart app will tell you when you need to use sun protection based on your location.
SunSmart app

Katie Lee, Research assistant, The University of Queensland and Monika Janda, Professor in Behavioural Science, The University of Queensland

This article is republished from The Conversation under a Creative Commons license. Read the original article.