Category: New Compounds

Christmas Came Early with These FDA Approvals

AI art generated by GenCraft.

After the stupendous effort for COVID vaccines and treatments, it may seem like other diseases were being neglected. Nevertheless, the US Food and Drug Administration suddenly had a fire lit underneath it, and got cracking with accelerated drug approvals. Now, 2023 seems to have brought plenty of new drugs to bolster the physician’s armamentarium – some are the first-ever treatment for their indications. Hopefully, with FDA and European Medicines Agency (EMA) approvals, South African approvals should not be too far behind.

Since the pandemic, hotly anticipated drugs have made a big splash or sunk without a trace. In 2021, semaglutide was approved for weight management, unleashing a wave of people using (and some abusing) the GLP-1 agonist for weight loss. Adagrasib, which targets KRAS, previously thought undruggable, was a major advance for the treatment of non-small-cell lung cancer and was one of a few notable new non-COVID pharmaceuticals.

Aducanumab/Aduhelm was the top tip for new drugs in 2021, but turned out to be an absolute debacle: it wound up being an astronomically expensive, mostly ineffective drug with significant side effects. There were even questions raised over how it got approved in the first place.

Alzheimer’s disease

Last year, Aduhelm seemed like yet another false start in the long battle against Alzheimer’s disease. This year though, it looks like help finally arrived for fight against the dreaded neurodegenerative disease with not one but two breakthrough drugs, both  antiamyloid antibodies.

Up first is lecanemab/Leqembi from Eisai/Biogen. It targets the buildup of amyloid proteins in the brain, which otherwise lead to the formation of amyloid plaques and neurofibrillary tangles of tau protein, the hallmarks of the disease.

The other candidate is donanemab, which did not secure FDA approval last year, after pharma company Eli Lilly witnessed the disaster that was Aduhelm. It did show a reduction in decline in one measure of Alzheimer’s disease but not another, so its effects are a mixed bag.

Like Aduhelm, donanemab and lecanemab both have a serious downside: brain swelling, which claimed the lives of at three donanemab trial participants.


Previously minimised by the pandemic’s social distancing and routine masking, respiratory syncytial virus (RSV) experienced a resurgence in the wake of lifting these restrictions. RSV afflicts primarily those over 60 and young children. Among those 65 and older with RSV in the US, the Centers for Disease Control estimated 120 000 annual hospitalisations, with up to 10 000 of whom dying. Among children under 5, the figures are 58 000 annual hospitalisations and 100 to 300 deaths. Historically, RSV vaccine developments wound up being ineffective. Fortunately, this year saw the first approval for an RSV vaccine. A 120µg dose of their Arexvy vaccine produced statistically significant and clinically meaningful reductions in cases of lower respiratory tract disease caused by RSV in adults aged 60 years and older. Pfizer and Moderna are hot on HSK’s heels with their own vaccine applications.

Age-related macular degeneration

Apellis got an approval for pegcetacoplan this year, for geographic atrophy (GA) secondary to age-related macular degeneration, in its intravitreal injection. This is the first and so far only treatment for this indication. “The approval of SYFOVRE is the most important event in retinal ophthalmology in more than a decade,” said Eleonora Lad, MD, PhD, lead investigator for the phase 3 study. “Until now, there have been no approved therapies to offer people living with GA as their vision relentlessly declined. With SYFOVRE, we finally have a safe and effective GA treatment for this devastating disease, with increasing effects over time.”

Interestingly, Apellis also got an approval for paroxysmal nocturnal haemoglobinuria (PNH) with a patient-injectable version of pegcetacoplan. The disease results from the destruction of red blood cells by the immune system.


Abbvie and Genmab’s epcoritamab, for certain cases of large B-cell lymphoma (LBCL), got accelerated FDA and EMA approval earlier this year. The FDA has also granted accelerated approval to Roche’s glofitamab. The drugs bind to binding to CD20 on malignant B cells and CD3 on T cells to kill cancer cells, creating an effect like CAR-T cell therapy but without the complexity (and presumably, cheaper too).

Major depressive disorder, postpartum depression

Mental health is full of gaps needing to be filled by effective treatments. Not much has made been added for depression since selective serotonin reuptake inhibitors (SSRIs) came onto the market in the 1990s. Zuranolone, from Biogen and Sage Therapeutics, is the first oral treatment for postpartum depression, which previously was treated only by IV injection in a healthcare facility. Unlike slow-acting SSRIs, this treatment, which targets the GABA-A receptor, is a short course.

Inflammatory bowel disease

There has been a steady drip of new biologic drugs for inflammatory diseases, such as bimekizumab (psoriasis and deucravacitinib which recently received FDA approval. Eli Lilly entered this crowded marketplace with ixekizumab. Now, after trouncing Novartis’ Cosentyx for psoriasis with its own mirikizumab, it pulled its application for that indication and switched it to ulcerative colitis – beating about a dozen competitors to be the first IL-23 inhibitor. It aims to get an approval for Crohn’s disease in 2025. Pfizer’s etrasimod for ulcerative colitis got approval in October 2023, and should receive EMA approval in 2024. Its phase 3 trial achieved 27% remission versus 7.4% for placebo.

Pulmonary arterial hypertension

Last is sotatercept, a new drug for pulmonary arterial hypertension (PAH), which previously had no real treatment. Unlike the current therapy aimed at simply dilating blood vessels, sotaracept targets BMPR-II signalling, addressing the cause of PAH. It earned a priority preview by the FDA based on its phase 3 trial data, with possible approval by March 2024.

Nanoparticles from Coffee Grounds could Stall Neurodegenerative Disease Development

Photo by Mike Kenneally on Unsplash

Researchers may potentially have found a preventive solution for neurodegenerative disorders in the most unlikely of sources: used coffee grounds. The researchers found caffeic-acid based Carbon Quantum Dots (CACQDs) have the potential to protect brain cells from the damage caused by several neurodegenerative diseases – if the condition is triggered by factors such as obesity, age and exposure to pesticides and other toxic environmental chemicals.

Carbon Quantum Dots are essentially simple nanoparticles made of carbon that have found a growing number of applications, including bioimaging thanks to its fluorescent properties and as photochemical catalysts. Their active surfaces can be doped with different elements for desired effects, are biocompatible and can be produced simply from a range of organic substances such as lemon juice and used tea leaves.

The University of Texas at El Paso team behind the study was led by Jyotish Kumar, a doctoral student in the Department of Chemistry and Biochemistry, and overseen by Mahesh Narayan, PhD, a professor and Fellow of the Royal Society of Chemistry in the same department. Their work is described in the journal Environmental Research.

“Caffeic-acid based Carbon Quantum Dots have the potential to be transformative in the treatment of neurodegenerative disorders,” Kumar said.

“This is because none of the current treatments resolve the diseases; they only help manage the symptoms. Our aim is to find a cure by addressing the atomic and molecular underpinnings that drive these conditions.”

Neurodegenerative diseases, when they are in their early stages and are caused by lifestyle or environmental factors, share several traits.

These include elevated levels of free radicals in the brain, and the aggregation of fragments of amyloid-forming proteins that can lead to plaques or fibrils in the brain.

Kumar and his colleagues found that CACQDs were neuroprotective across test tube experiments, cell lines and other models of Parkinson’s disease when the disorder was caused by a pesticide called paraquat.

The CACQDs, the team observed, were able to remove free radicals or prevent them from causing damage and inhibited the aggregation of amyloid protein fragments without causing any significant side effects.

The team hypothesises that in humans, in the very early stage of a condition such as Alzheimer’s or Parkinson’s, a treatment based on CACQDs can be effective in preventing full-on disease.

“It is critical to address these disorders before they reach the clinical stage,” Narayan said.

“At that point, it is likely too late. Any current treatments that can address advanced symptoms of neurodegenerative disease are simply beyond the means of most people. Our aim is to come up with a solution that can prevent most cases of these conditions at a cost that is manageable for as many patients as possible.”

Caffeic acid belongs to a family of compounds called polyphenols, which are plant-based compounds known for their antioxidant, or free radical-scavenging properties. Caffeic acid is unique because it can penetrate the blood-brain barrier and is thus able to exert its effects upon the cells inside the brain, Narayan said.

In the simple one-step ‘green chemistry’ method, the team ‘cooked’ caffeic acid at 230°C for two hours to reorient the caffeic acid’s carbon structure and form CACQDs. The CACQDs were then extracted according to a molecular weight cutoff of 1kDa.

The sheer abundance of coffee grounds is what makes the process both economical and sustainable, Narayan said.

Source: University of Texas at El Paso

Autofluorescent Compound Paints a Bright Future for Antimalarial Research

Red Blood Cell Infected with Malaria Parasites Colourised scanning electron micrograph of red blood cell infected with malaria parasites (teal). The small bumps on the infected cell show how the parasite remodels its host cell by forming protrusions called ‘knobs’ on the surface, enabling it to avoid destruction and cause inflammation. Uninfected cells (red) have smoother surfaces. Credit: NIAID

New compounds are continuously required due to the risk of malaria parasites becoming resistant to the medicines currently used. A team of researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) combined the anti-malaria drug artemisinin with coumarin, and developed a compound from both bioactive plant-derived substances. This compound is also autofluorescent, making it particularly useful as it can be used for imaging in live cells.

The working group, led by Prof Dr Svetlana B. Tsogoeva, also discovered that the autofluorescent artemisinin-coumarin hybrids are able to destroy a certain drug-resistant malaria pathogen called Plasmodium palcifarum. They published their findings in the journal Chemical Science.

Artemisinin is a highly-effective and common ingredient for the manufacture of malaria medication gained from a plant called sweet wormwood (Artemisia annua L.). Coumarin is a secondary plant compound found in various plants.

In the development of drugs against malaria, active substances such as artemisinin are labelled with fluorescent substances in order to identify how they act against malaria pathogens in precise chronological order using imaging techniques.

Combining substances to achieve autofluorescence

A significant disadvantage of labeling with fluorescent substances is the fact that they alter how the medication works.

For example, this means that in certain circumstances cells infected with malaria absorb a drug like artemisinin differently after fluorescent marking than previously.

The solubility of the drug can also change. This was avoided by the development of autofluorescent hybrids, which are compounds made of two or more basic compounds that are inherently fluorescent and whose mode of action can be precisely observed using imaging techniques.

Active agent with special skills

The team decided to combine artemisinin with bioactive coumarins because coumarin derivatives also possess anti-malaria properties. They can also be easily chemically altered so that they become extremely fluorescent.

The researchers discovered that it was not only possible to observe the mode of action of this first autofluorescent artemisinin-coumarin hybrid in living red blood cells infected with P. falciparum.

In conjunction with Prof. Barbara Kappes (Department of Chemical and Biological Engineering, FAU) and Dr. Diogo R. M. Moreira (Instituto Gonçalo Moniz, Fiocruz Bahia, Brazil), they also discovered that the active agent was highly effective against P. falciparum strains in vitro that are resistant to chloroquin and other malaria drugs.

Above all, however, the new compound also proved highly effective against the malaria pathogens in vivo in mouse models.

With the creation of the first autofluorescent artemisinin-coumarin hybrid, the FAU researchers hope that they have laid the foundation for the development of further autofluorescent agents for treating malaria and have made significant process in overcoming multi-drug resistance in the treatment of malaria.

Source: Friedrich-Alexander-Universität Erlangen-Nürnberg

New Compound Outperforms Gabapentin for Pain Relief

Photo by Louis Reed on Unsplash

A new compound reversed four types of chronic pain in animal studies, according to new research published online in the Proceedings of the National Academy of Sciences (PNAS). It outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain.

Researchers led by NYU College of Dentistry’s Pain Research Center developed this small molecule, which binds to an inner region of a calcium channel to indirectly regulate it.

Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA – “the currency of the pain signal,” according to Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin and pregabalin, which are widely used to treat nerve pain and epilepsy.

Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel’s activity. However, like many pain medications, gabapentin use often comes with side effects.

“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging,” said Khanna, the senior author of the PNAS study. “Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain.”

Inside the channel

Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide – calcium channel-binding domain 3 (CBD3) – was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies.

Peptides are difficult to synthesise as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain.

“At that point, we realised that these two amino acids could be the building blocks for designing a small molecule,” said Khanna.

From 27 million to one

In collaboration with colleagues at the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would “match” the CBD3 amino acids.

The simulation narrowed the library down to 77 compounds, which the researchers experimentally tested to see if they lessened the amount of calcium influx. This further pared the pool down to nine compounds, which were assessed using electrophysiology to measure decreases in electrical currents through the calcium channels.

One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters.

“Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside. Our target, these two amino acids from CRMP2, is on the inside of the cell, and this indirect approach may be the key to our success,” said Khanna.

Four labs, four types of pain

Khanna’s lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice – and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1–10mg) than gabapentin (30 mg) to reduce pain.

To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with researchers at Virginia Commonwealth University, Michigan State University, and Rutgers University. Collaborators ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain – all successfully reversing pain, similar to gabapentin.

But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing.

What’s next

The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound’s safety and assess if tolerance develops.

Long-term, they hope to bring a CBD3063-derived drug to clinical trials in an effort to offer new options for safe and effective pain relief.

“Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain,” said Khanna.

Source: New York University

New Drug Effective for 3 of 4 Trial Patients with Relapsed Blood Cancer

Photo by National Cancer Institute on Unsplash

A new targeted drug, may offer a new treatment option for patients with blood cancers, including chronic lymphocytic leukaemia (CLL) and Non-Hodgkin lymphoma (NHL) whose disease has stopped responding to standard treatments.

In the first clinical trial of this drug in humans, nemtabrutinib was effective in three-fourths of cancer patients tested, without severe side effects. The results of the trial were published in the journal Cancer Discovery.

Haematologist and study lead investigator Jennifer Woyach, MD, notes that about half a dozen drugs are available to treat these B-cell cancers. Although most patients respond to these drugs initially, over time, many patients experience disease progression. The study was done by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

“Blood cancers that have relapsed after initial treatments can be difficult to treat, and even with our effective medications, some patients run out of standard treatment options.  In this trial, nemtabrutinib looks very promising for patients whose cancer has progressive after other treatments.” said Woyach, who is co-leader of the Leukemia Research Program at the OSUCCC – James.

How this drug therapy works

When an antigen, such as a virus or bacteria, enters the bloodstream, it triggers a set of signals in B-cells to produce antibodies. In some people, said Woyach, this process goes haywire. Instead of fighting infections, the B-cells begin to divide uncontrollably, resulting in cancer. Drugs against B-cell cancers work by binding to a key enzyme, called Bruton’s tyrosine kinase (BTK). This enzyme is involved in the signaling process. The drugs block the action of the enzyme, and as a result, the abnormal B-cells die.

In many patients, this effect is temporary with available drugs. Over time, the BTK enzyme to which the drugs bind mutates so they can no longer stop its action. Soon, the cancer returns. Nemtabrutinib was designed to bind to BTK even in the presence of common mutations that make other BTK inhibitors stop working. It also binds to a number of proteins besides BTK that are important in B cell cancers. These two properties made this drug very appealing to study in this patient population.

Study methods and results

The researchers tested the new drug on 47 patients who have had at least two prior therapies for their blood cancer. Over half of these patients had relapsed CLL, while the others had NHL. The researchers gave these patients one pill of nemtabrutinib every day, with different doses along the trial. They observed the patients’ response to the drug over time and monitored them for side effects.

The study found more than 75% of the patients with relapsed CLL responded to the drug, at an optimal dose of 65mg. These included patients who had mutations in BTK. Most patients remained cancer free for at least 16 months during the trial. While all patients experienced some side effects – which is common with chemotherapeutic drugs – many of these were minor and manageable, proving that the drug was also very safe.

“The drug is being moved to larger and more definitive trials, where it will be compared against other standard-of-care drugs, and in combination with other active medications,” said Woyach.

The blood cancers investigated in this trial affect B lymphocytes, which is a cell that is responsible for producing antibodies and fighting infections. CLL is the most common leukaemia making up a quarter of leukaemia cases among adults, and NHL accounts for 4% of all cancers in the United States.

Source: Ohio State University

A New Drug Could Provide Hope in Treatment-resistant Epilepsy

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In cases where standard therapies fail, an in-development drug called XEN1101 reduces seizure frequency by more than 50% in some patients and in some cases eliminates them, according to a new study published in JAMA Neurology. Unlike several treatments that must be started at low doses and slowly ramped up, the new drug can safety be taken at its most effective dose from the start, the authors say.

Focal seizures, the most common type seen in epilepsy, occur when nerve cells in a particular brain region send out a sudden, excessive burst of electrical signals. Along with seizures, this uncontrolled activity can lead to abnormal behaviour, periods of lost awareness, and mood changes. While many available therapies control or reduce seizures, they fail to stop seizures in about one-third of patients and may cause harsh side effects, experts say.

Led by researchers at NYU Grossman School of Medicine, a new clinical trial found that patients who added XEN1101 to their current antiseizure treatments saw a 33% to 53% drop in monthly seizures, depending on their dose. By contrast, those given a placebo had on average 18% fewer seizures during the treatment phase of the trial, which lasted eight weeks. Most patients then volunteered to extend the trial, with about 18% of those treated with the new drug remaining entirely seizure free after six months, and about 11% having no seizures after a year or longer.

“Our findings show that XEN1101 may offer a swift, safe, and effective way to treat focal epilepsy,” said study lead author, neurologist Jacqueline French, MD. “These promising results offer hope for those who have struggled for decades to get their symptoms under control.”

French, a professor in the Department of Neurology at NYU Langone Health, notes that XEN1101 was well tolerated by the study participants, who reported side effects similar to other antiseizure treatments, including dizziness, nausea, and fatigue, and the majority felt well enough to continue the regimen. Another benefit of the drug, she adds, is that it takes more than a week to break down, so levels in the brain remain consistent over time. This steadiness allows the treatment to be started at full strength and helps to avoid dramatic spikes that worsen side effects, and dips that allow seizures to return. This lengthy breakdown time also allows for a “grace period” if a dose is accidently skipped or taken late.

XEN1101 is part of a class of chemicals called potassium-channel openers, which avert seizures by boosting the flow of potassium out of nerves, stopping them from firing. French notes that while other drugs of this kind have been explored for epilepsy patients in the past, such treatments were taken out of use because the compounds were later found to gradually build up in the skin and eyes, prompting safety concerns, the researchers say.

Meanwhile, XEN1101 combines the effectiveness of potassium-channel openers with the safety of more traditional drugs, says French, who is also a member of NYU Langone’s Comprehensive Epilepsy Center.

For the study, which included 285 men and women with epilepsy and ran from January 2019 to September 2021, the research team recruited adults with epilepsy who had already tried and stopped taking an average of six drugs that failed to treat their focal seizures. Patients in the trial had to have experienced at least four episodes a month despite ongoing treatment to qualify. The patients were randomly provided either a daily oral capsule of XEN1101 (in 10mg, 20mg, or 25mg doses) or placebo.

Among the results, the trial revealed no signs of dangerous side effects such as heart problems, allergic reactions, or concerning skin discolourations. However, French says that the research team plans to expand the number of patients exposed to the drug and monitor for potential issues that could arise in the long term, or include specific groups of people, such as pregnant women. In addition, the team also intends to explore XEN1101 for other types of seizures, including those that broadly affect the brain at the same time (generalised seizures).

“Our study highlights the importance of finding as many therapeutic options as possible for those who suffer from seizures,” says French. “Since everyone responds differently, treating epilepsy cannot be a one-size-fits-all approach.”

Source: NYU Langone Health / NYU Grossman School of Medicine

Eyedrops instead of Injections for Age-related Macular Degeneration

Retina showing reticular pseudodrusen. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Credit: National Eye Institute

A new compound potentially could offer an alternative to injections for the millions of people who suffer from wet age-related macular degeneration (AMD). The condition causes vision loss due to the uncontrolled growth and leakage of blood vessels in the back of the eye. A new paper in Cell Reports Medicine finds that a small-molecule inhibitor can reverse damage from AMD and promote regenerative and healing processes.

The drug can also be delivered via eyedrops – an improvement over current treatments for AMD, which require repeated injections into the eye.

“The idea was to develop something that can be more patient-friendly and doesn’t require a visit to the doctor’s office,” said lead researcher Yulia Komarova, associate professor of pharmacology at University of Illinois Chicago.

Komarova’s compound targets the protein End Binding-3 in endothelial cells, which line the inside of blood vessels. In the new study, the researchers looked at whether inhibiting EB3 function could stop the damaging leakage associated with wet AMD.

Using computational drug design methods, the team developed a small molecule drug, End Binding-3 inhibitor (EBIN), that could be delivered externally via eyedrops instead of by injection. They then tested its effectiveness in animal models of wet AMD, finding that twice-daily treatment reduced eye damage within 2–3 weeks.

Further investigation found that the inhibitor worked by rolling back aging-related genetic modifications. Aging causes inflammation and hypoxia in the eye that leads to changes in gene expression associated with the cellular effects and symptoms of wet AMD. Komarova and colleagues found that the EB3 inhibitor they developed reversed these epigenetic changes, restoring gene expression to a normal, healthy state.

“We reduce the effects of the stressor on endothelial cells and we improve regenerative processes, accelerating healing,” Komarova said. “That can be tremendous for the function of the cells.”

Because blood vessel leakage and hypoxic stress also drive many other medical conditions, Komarova’s group is interested in testing the inhibitor in models of acute lung injury, diabetic retinopathy, stroke, heart disease and even the general effects of aging on the brain. They are also exploring whether an implantable lens, similar to a contact lens, could deliver the drug to the eye more effectively than eyedrops.

Source: University of Illinois Chicago

Fast-acting Nasal Spray Could Treat Tachycardia Episodes

Photo by Stephen Andrews

A fast-acting drug delivered as a nasal spray may someday allow patients with intermittent tachycardia to treat it themselves as soon as they develop symptoms, according to new research published in the Journal of the American Heart Association. The drug is still under development and awaiting approval in the US by the Food and Drug Administration.

“This is a potential new and exciting option for patients to safely self-treat their rapid heartbeat without direct medical supervision to avoid emergency room visits and medical interventions,” said lead author James E. Ip, MD, an associate professor of clinical medicine at Weill Cornell Medicine at New York-Presbyterian Hospital.

About 1 in 300 people in the United States experience intermittent periods paroxysmal supraventricular tachycardia, a condition characterised by rapid heartbeat (>100bpm, and more typically 150–200 bpm) in the lower chambers of the heart.

The standard treatment during an episode is to perform vagal manoeuvres, one of which is done by trying to bear down, achieved by breathing out with stomach muscles but not letting air out the nose or mouth. This can make the vagus nerve slow electrical conduction through the atrioventricular (AV) node, which regulates the timing of the electrical pulses to the lower portion of the heart. If the self-administered vagal manoeuvres are not effective (which happens about 20–40% of the time), the person should seek immediate treatment of intravenous medication at an emergency room to return the heart rate to normal. In the United States, about 50,000 emergency room visits a year are for paroxysmal supraventricular tachycardia, Ip said.

In a previous study, people with the disorder treated themselves with either etripamil or a placebo nasal spray for a single episode of rapid heartbeat. Participants applied an electrocardiogram (ECG) patch at the onset of symptoms, did a vagal manoeuvre and self-administered the nasal spray if the rapid heartbeat continued – keeping the ECG patch on for at least five hours. In that study, the first time that etripamil was used without direct supervision, normal heart rhythms were restored within 30 minutes in 54% of patients, compared to 35% with placebo, and the medication was found to be safe and well tolerated. The ECG patch is a wearable heart monitor that has a small device with an adhesive that sticks on the chest skin surface and is wirelessly connected to a cell phone to transmit the ECG data.

All people in that randomised trial were invited to participate in the current open-label study that allowed patients to self-treat with etripamil during multiple episodes of paroxysmal supraventricular tachycardia (PSVT). Of the 169 patients enrolled, 105 self-administered at least one dose of etripamil (70mg) during the median 232-day study period.

The new study found:

  • Etripamil restored heart rate to normal within 30 minutes in 60.2% of the 188 verified PSVT episodes, and within an hour in 75.1% of the episodes.
  • Of the 40 participants who self-treated two episodes, 63.2% responded to the medication within 30 minutes. Nine people (23%) did not convert to a normal heart rate on either episode, and 21 (53%) converted to normal heart rate on both episodes.
  • Safety was assessed regardless of whether the episode was confirmed by ECG. Thirty-four participants (32.4%) reported one or more side effects from the medication, most commonly mild-to-moderate nasal congestion or discomfort, or a runny nose. There were no serious heart-related adverse events.

“There are no great options for patients to self-treat paroxysmal supraventricular tachycardia, and this condition can cause significant distress and anxiety,” Ip said. “Similar to an albuterol inhaler for asthma patients or an epinephrine pen for patients that have severe allergies or anaphylaxis, etripamil nasal spray may be a great option for people who have paroxysmal supraventricular tachycardia.

Source: American Heart Association

Plant Compound could Prove to be a Potent Tool against Candida

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A new study published in the journal ACS Infectious Diseases has found that a natural compound found in many plants inhibits the growth of drug-resistant Candida fungi – including its most virulent species, Candida auris, an emerging global health threat.

Led by Emory University researchers, the study used in vitro experiments that showed that the natural compound, a water-soluble tannin known as PGG, blocks 90% of the growth in four different species of Candida fungi. The researchers also discovered the mechanism by which PGG inhibits the growth: It grabs up iron molecules, essentially starving the fungi of an essential nutrient.

By starving the fungi rather than attacking it, the PGG mechanism does not promote the development of further drug resistance, unlike existing antifungal medications. In vitro testing also showed minimal toxicity of PGG to human cells.

“Drug-resistant fungal infections are a growing healthcare problem but there are few new antifungals in the drug-development pipeline,” says Cassandra Quave, senior author of the study and assistant professor at Emory University. “Our findings open a new potential approach to deal with these infections, including those caused by deadly Candida auris.”

C. auris is often multidrug-resistant and has a high mortality rate, leading the Centers for Disease Control and Prevention (CDC) to label it a serious global health threat.

“It’s a really bad bug,” says Lewis Marquez, first author of the study and a graduate student in Emory’s molecular systems and pharmacology programme. “Between 30 to 60% of the people who get infected with C. auris end up dying.”

An emerging threat

Some species of Candida, a yeast commonly found on the skin or in the digestive tract, can cause infection, which can be invasive and life-threatening. Immunocompromised people, including many hospital patients, are most at risk for invasive Candida infections, which are rapidly evolving drug resistance.

In 2007, the new Candida species, C. auris, emerged in a hospital patient in Japan. Since then, C. auris has caused health care-associated outbreaks in more than a dozen countries around the world with more than 3000 clinical cases reported in the United States alone.

A ‘natural’ approach to drug discovery

Quave is an ethnobotanist, studying how traditional people have used plants for medicine to search for promising new candidates for modern-day drugs. Her lab curates the Quave Natural Product Library, which contains 2500 botanical and fungal natural products extracted from 750 species collected at sites around the world.

“We’re not taking a random approach to identify potential new antimicrobials,” Quave says. “Focusing on plants used in traditional medicines allows us to hone in quickly on bioactive molecules.”

Previously, the Quave lab had found that the berries of the Brazilian peppertree, a plant used by traditional healers in the Amazon for centuries to treat skin infections and some other ailments, contains a flavone-rich compound that disarms drug-resistant staph bacteria. They had also found that the leaves of the Brazilian peppertree contain PGG, a compound that has shown antibacterial, anticancer and antiviral activities in previous research.

A 2020 study by the Quave lab, for instance, found that PGG inhibited growth of Carbapenem-resistant Acinetobacter baumannii, a bacterium that infects humans and is categorised as one of five urgent threats by the CDC.

The Brazilian peppertree is a member of the poison ivy family. “PGG has popped up repeatedly in our laboratory screens of plant compounds from members of this plant family,” Quave says. “It makes sense that these plants, which thrive in really wet environments, would contain molecules to fight a range of pathogens.”

Experimental results

The Quave lab decided to test whether PGG would show antifungal activity against Candida.

In vitro experiments demonstrated that PGG blocked around 90% of the growth in 12 strains from four species of CandidaC. albicans, multidrug-resistant C. auris and two other multidrug-resistant non-albicans Candida species.

PGG is a large molecule known for its iron-binding properties. The researchers tested the role of this characteristic in the antifungal activity.

“Each PGG molecule can bind up to five iron molecules,” Marquez explains. “When we added more iron to a dish, beyond the sequestering capacity of the PGG molecules, the fungi once again grew normally.”

Dish experiments also showed that PGG was well-tolerated by human kidney, liver and epithelial cells.

“Iron in human cells is generally not free iron,” Marquez says. “It is usually bound to a protein or is sequestered inside enzymes.”

A potential topical treatment

Previous animal studies on PGG have found that the molecule is metabolised quickly and removed from the body. Instead of an internal therapy, the researchers are investigating its potential efficacy as a topical antifungal.

“If a Candida infection breaks out on the skin of a patient where a catheter or other medical instrument is implanted, a topical antifungal might prevent the infection from spreading and entering into the body,” Marquez says.

The researchers will bext test PGG as a topical treatment for fungal skin infections in mice.

Meanwhile, Quave and Marquez have applied for a provisional patent for the use of PGG for the mitigation of fungal infections.

“These are still early days in the research, but another idea that we’re interested in pursuing is the potential use of PGG as a broad-spectrum microbial,” Quave says. “Many infections from acute injuries, such as battlefield wounds, tend to be polymicrobial so PGG could perhaps make a useful topical treatment in these cases.”

Source: Emory University

Doing the Impossible: New Drug Kills 100% of Solid Tumours by Hitting ‘Undruggable’ Target

Assembled human PCNA (PDB ID 1AXC), a sliding DNA clamp protein that is part of the DNA replication complex and serves as a processivity factor for DNA polymerase. The three individual polypeptide chains that make up the trimer are shown. Source: Wikimedia CC0

A ‘cure for cancer’ has long been something of a holy grail for medical research – but experience has shown that cancers are highly individualised and respond differently to therapy, adapting to resist them. Now, in an early study, researchers have tested a cancer drug that kills all solid cancer tumours while leaving other cells unharmed and resulting in no toxicity. The new molecule targets a common key cancer cell protein, the proliferating cell nuclear antigen (PCNA), that is key to helping them grow and metastasise – a target previously believed to be ‘undruggable’.

The new drug, AOH1996, was tested in vitro against 70 different cancer cell lines, including breast, prostate, brain, ovarian, cervical, skin, and lung cancer. It proved effective against all of them, as well as sparing healthy cells. What’s more, developing resistance against the drug is unlikely due to the nature of PCNA as a mistranslation rather than a mutation. The results were published in Cell Chemical Biology. Instructions for synthesis were included in supplementary material.

The last great breakthrough in cancer treatment was immunotherapy, and since then cancer research has looked for the next big leap. A search of journal articles in the Pubmed database showed that “cancer” has grown from 6% of all results in 1950 to 16% by 2016. More recent development in cancer therapies has included gene-based approaches, naked nucleic acids based therapy, targeting micro RNAsoncolytic virotherapy, suicide gene based therapy, targeting telomerasecell mediated gene therapy, and CRISPR/Cas9 based therapy.

Shutting down the hub

The research was led by Dr Linda Malkas, a professor at City of Hope Hospital, who said that the molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells unaffected. Animal models also showed a reduction of tumour burden with no apparent adverse effects, with the no observed adverse effect level (NOAEL) calculated being six times higher than the administered dose.

She explained the drug in simple terms to the Daily Mail: “Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant,” she said. “PCNA is like a major airline terminal hub containing multiple plane gates.

“Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells. Our cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells.”

Dr Malkas said results so far have been ‘promising’ as the molecule can suppress tumour growth on its own or in combination with other cancer treatments without resulting in toxicity.

The development of AOH1996 is the culmination of nearly two decades of work by City of Hope Hospital in Lose Angles.

Decades in the making

PCNA in breast cancer was identified as a potential target in 2006 since it is an isomer, allowing antibodies to target it. The researchers’ first attempts with antibodies to target PCNA were unsuccessful as these were too big to penetrate into solid tumours. Next, they tried a small molecule, which appeared to work in vitro but in vivo proved to have a half-life of only 30 minutes. But they were able to tweak that molecule and arrive at the current drug, AOH1996. It was named after Anna Olivia Healy who died in 2005 from neuroblastoma, and she became the inspiration for the research.

“She died when she was only 9 years old from neuroblastoma, a children’s cancer that affects only 600 kids in America each year,” Malkas said. “I met Anna’s father when she was at her end stages. I sat him down for two hours in my office and showed him all of my data on this protein I had been studying in cancer cells.”

At the time, Dr Malkas was researching breast cancer, studying a protein found in cancer cells but not normal cells. Dr Malkas eventually took Anna’s father, Steve, and his wife, Barbara, to see her lab.

“[Steve] asked if I could do something about neuroblastoma and he wrote my lab a cheque for $25 000,” Dr Malkas said. “That was the moment that changed my life – my fork in the road. I knew I wanted to do something special for that little girl.”