Tag: nitrous oxide

Scientists Identify New Cause of Diabetes – and Potential Treatment Target

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Researchers have identified an enzyme that blocks insulin produced in the body – a discovery that could provide a new target to treat diabetes. Their study, published the journal Cellfocuses on nitric oxide, which dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions.

How nitric oxide performs these activities had long been a mystery.

The researchers at Case Western Reserve University and University Hospitals discovered a novel “carrier” enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action.

They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes.

Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases.

“We show that blocking this enzyme protects from diabetes, but the implications extend to many diseases likely caused by novel enzymes that add nitric oxide,” said the study’s lead researcher Jonathan Stamler, professor at the Case Western Reserve School of Medicine.

“Blocking this enzyme may offer a new treatment.”

Given the discovery, next steps could be to develop medications against the enzyme, he said.

Many human diseases, including Alzheimer’s, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide binding excessively to key proteins.

With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus.

With diabetes, the body often stops responding normally to insulin.

The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems.

Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease.

But the reason that insulin stops working isn’t well understood.

Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can’t be targeted specifically, Stamler said.

“This paper shows that dedicated enzymes mediate the many effects of nitric oxide,” he said. “Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases.”

Source: Case Western Reserve University

Scientists Test A Potential New Therapy for Preeclampsia

Pregnant with ultrasound image
Source: Pixabay

Researchers have proposed a new therapy for preeclampsia that corrects the defects identified in placental cells, and restores placental and foetal weight, which they report in the journal Redox Biology. The treatment, tested in two rodent models, successfully lowers blood pressure in the mother and resolves the characteristic preeclampsia symptoms of proteinuria and cardiovascular abnormalities.

Preeclampsia is a placental dysfunction that affects approximately 2 to 8% of pregnant women worldwide. It can have potentially complications for mother and child, and longer-term consequences for the mother. Preeclampsia symptoms are primarily arterial hypertension, proteinuria, abnormal coagulation in the placenta, cardiovascular abnormalities in the mother and foetal growth restriction. Treatments for preeclampsia are limited and mostly involve aspirin as a preventative measure, reducing the procoagulant state in the placenta and partly relieving pressure on the vascular network.

Preeclampsia is characterised by a defective placenta caused by trophoblast dysfunction. Trophoblasts are placental cells that help organise and manage the vascular network which provides the essential resources for foetal growth. At the molecular level, preeclampsia is characterised by an uncontrolled increase in oxidative stress, with excessive production of various reactive species including reactive oxygen and nitrogen species. There is a genetic component: the first gene to be identified as being implicated in the genetic forms of preeclampsia was the STOX1 transcription factor, which controls the expression of thousands of genes, especially those involved in the production of nitric oxide (NO).

In a transgenic mouse model, high accumulation of STOX1 in the placenta induced a preeclampsia-like syndrome. In preeclampsia, NO, a powerful vasodilator that promotes blood flow to the placenta, is mobilised to produce potentially toxic molecules (nitrosative stress) and its levels become insufficient in the placental vascular network, affecting trophoblast function and the vascular network and destabilising other reactive species. This creates a vicious circle and causes uncontrollable oxidative/nitrosative stress with multiple complications, also affecting maternal blood vessel cells, with potentially fatal consequences.

NO is produced by a family of enzymes known as nitric oxide synthases (NOSs). Finding a way of restoring NO production in the placenta via NOSs could represent an effective new therapy to treat preeclampsia. A years-long collaboration gave rise to a potential solution. The scientists’ research was based on trophoblasts overexpressing STOX1 and on two rodent models of preeclampsia, one mimicking early-onset forms via placental overexpression of STOX1 and the other mimicking late-onset forms by partial occlusion of the lower abdominal aorta.

The research revealed a cascade of events that ultimately led the scientists to propose a new therapy. Treating trophoblasts with BH4 (tetrahydrobiopterin, a cofactor that stabilises the NOS enzyme producing NO) corrected the defects identified in these cells, restoring production of NO rather than potentially toxic molecules. More importantly, administering BH4 to the two preclinical rodent models restored placental and foetal weight. Finally, in the early-onset STOX1 preclinical model with significant arterial hypertension and proteinuria, the BH4 treatment corrected blood pressure, excess protein in urine, and cardiovascular abnormalities in the mother. The results even suggest that the treatment may be effective in addressing the long-term effects of preeclampsia on mothers (vascular abnormalities in the brain, kidneys, heart and liver).

This research is the first step towards the development of a therapy for preeclampsia. Genetic analyses of placentas treated with BH4 showed that it corrects the expression of several genes disrupted by excess STOX1 differently than the deregulation induced by aspirin in the placenta. The scientists therefore propose that a treatment combining BH4 and aspirin could be the ultimate therapeutic solution for many cases of preeclampsia. This hypothesis needs to be validated in clinical trials.

Source: Institut Pasteur

Study Finds No Adverse Effects Denying Nitrous Oxide in Labour

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Birthing women denied nitrous oxide(N20) to relieve labour pain as a result of the COVID pandemic received opioids instead, without any adverse outcomes for mother or child, according to a new study published in the Australian and New Zealand Journal of Obstetrics and Gynaecology. Some anaesthetists have also argued for reducing N20 use as it is a greenhouse gas.

The study, conducted at Lyell McEwin Hospital in Australia, looked at the impact of withholding nitrous oxide (N20), a decision adopted by many hospitals worldwide over fears of virus transmission from the aerosol-generating procedure.

Anaesthetist Professor Bernd Froessler and colleagues compared patient notes for all 243 women birthing at Lyell McEwin over a seven week period in March/April 2020, half of whom did not have access to N20.

They found that although opioid use “significantly increased” when N20 was withheld, there was no increase in epidural use and no change in labour duration, Caesarean section rates, birthing complications or newborn alertness.

Nitrous oxide is used by more than 50% of Australian women to relieve pain in labour, followed by epidurals (40%) and opioids (12%), according to the Australian Institute of Health and Welfare.

However, N20 represents 6% of global greenhouse gas emissions, with 1% due to medical use (ie, around 0.06% of total global warming is due to medical N20). This has led to a debate in medical circles whether it should be replaced with other methods of pain relief.

Many obstetricians argue that effective pain relief in childbirth should be the priority, particularly given the low percentage of emissions, but the Australian and New Zealand College of Anaesthetists has advocated for a reduction in N20 use in a bid to improve environmental sustainability in anaesthesia.

“Obviously no-one wants to deprive labouring women of adequate and easy pain relief but given there are other analgesic options, including epidurals and opioids, perhaps these could be considered,” said Prof Froessler.

UniSA statistician and researcher Dr Lan Kelly said that the findings should reassure women that pain relief besides N20 does not compromise their health or their baby’s.

However, in a recent Sydney Morning Herald article, principal midwifery officer at the Australian College of Midwives, Kellie Wilton, said mothers should not be made to feel guilty about their pain relief choices and suggested hospitals could introduce nitrous oxide destruction systems to allow for its ongoing use.

When nitrous oxide destruction systems were introduced in Swedish hospitals, the carbon footprint from the gas was halved.

Source: University of South Australia

Nitrous Oxide Safe and Effective Therapy for Severe COVID in Pregnancy

Pregnant with ultrasound image
Source: Pixabay

High dose inhaled nitric oxide gas (iNO) is a safe and effective respiratory therapy for pregnant women hospitalised with severe COVID pneumonia, resulting in faster weaning from oxygen and shorter hospital stay, according to a study published in Obstetrics & Gynecology. Massachusetts General Hospital (MGH) researchers reported that the addition of twice-daily nitric oxide to standard of care oxygen therapy decreased the respiratory rate of pregnant women with low oxygenation levels of the blood without causing any side effects.

“To date, very few respiratory treatments to complement supplemental oxygenation in COVID pregnant patients have been tested,” explained the study’s senior author, Lorenzo Berra, MD. “Investigators from all four medical centers that participated in our study agreed that administration of high dose nitric oxide through a snug-fitting mask has enormous potential as a new therapeutic strategy for pregnant patients with COVID.”

Pneumonia triggered by COVID is particularly threatening to pregnant women since it may quickly progress to hypoxaemia, requiring hospitalisation and cardiopulmonary support. “Compared to non-pregnant female patients with COVID, pregnant women are three times more likely to need intensive care unit admission, mechanical ventilation, or advanced life support, and four times more likely to die,” noted lead author Carlo Valsecchi, MD. “They also face a greater risk of obstetric complications such as preeclampsia, preterm delivery, and stillbirth.”

Nitric oxide is a therapeutic gas that was initially approved by the U.S. Food and Drug Administration in 1999 for inhalation treatment of intubated and mechanically ventilated newborns with hypoxic respiratory failure. With MGH driving many early studies, iNO in high concentrations was also shown to be effective as an antimicrobial in reducing viral replication of SARS-CoV-1 and, more recently, SARS CoV-2. During the first wave of COVID, MGH treated six non-intubated pregnant patients with iNO at high doses of up to 200 parts per million (ppm). Favourable outcomes with iNO led MGH clinicians to offer this treatment to other pregnant patients, and motivated the present study.

Researchers and clinicians from multiple departments in four hospitals – including critical care medicine, respiratory care, and maternal foetal medicine – studied 71 pregnant patients with severe COVID pneumonia admitted to these hospitals, 20 of whom received iNO200 twice daily. The study found that iNO therapy at this dosage, when compared to standard of care alone, resulted in reductions in the need for supplemental oxygen and in hospital and ICU lengths of stay. No adverse events related to the intervention were reported in either mothers or their babies.

“Being able to wean patients from respiratory support quicker could have other profound implications, including reducing stress on women and their families, lowering the risk of hospital-acquired infections, and relieving the burden on the health care system,” noted Dr Berra. “Above all, our study supports the safety of high dose nitric oxide in the pregnant population, and we hope more physicians will consider incorporating it into carefully monitored treatment regimens.”

Source: Massachusetts General Hospital

Low Doses of Nitrous Oxide can Relieve Stubborn Depression

A small dose of nitrous oxide may be able to relive the symptoms of medication-resistant depression. Photo by Mockup Graphics on Unsplash

A new study at the University of Chicago Medicine and Washington University found that inhaling low doses of nitrous oxide gas rapidly relieved symptoms of treatment-resistant depression, with few adverse side effects. They found that this was as effective as higher doses of the gas, with fewer unpleasant side effects.

These findings add to the growing body of evidence of non-traditional treatments that may be a viable option for patients with depression that is unresponsive to typical antidepressant medications. It may also be a fast-acting and effective treatment option for patients in crisis.

Often called ‘laughing gas’, nitrous oxide is widely used as an anaesthetic, providing short-term pain relief in dentistry, emergency response and surgery.

A previous study tested a one-hour inhalation session with 50% nitrous oxide gas, which resulted in rapid improvements in depressive symptoms that lasted for at least 24 hours. However, several patients reported negative side effects, including nausea, vomiting and headaches.

“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anaesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

The new study used a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that the halved-concentration treatment was nearly as effective as 50% nitrous oxide, but there were only one quarter of the negative side effects.

Additionally, researchers tested the patients’ depression scores following treatment over a longer period of up to two weeks compared to 24 hours in the previous protocol. Surprisingly, they found that after only a single administration, some patients had improvements that lasted for the entire follow-up period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Dr Nagele. “This has never been shown before. It’s a very cool finding.”

These findings point to nitrous oxide being a promising, rapid and effective treatment for those suffering from severe depression which is unresponsive to the usual medication such as SSRIs.

“A significant percentage — we think around 15% — of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine. “These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

Despite its ‘laughing gas’ name, patients actually fall asleep after such a low dose.

“They’re not getting high or euphoric, they get sedated,” Dr Nagele said.

Non-traditional treatments for depression faces an uphill battle for acceptance in the mainstream, though researchers hope that the findings from this and similar studies will help open physicians’ minds towards these other possible solutions.

“These have just been pilot studies,” said Dr Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

With broader public acceptance, Dr Nagele hopes that these results help those patients who are struggling to find adequate therapies for their depression.

“There is a huge unmet need,” he said. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”

Source: University of Chicago Medical Center

Journal information: P. Nagele et al., “A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression,” Science Translational Medicine (2021).