Category: New Compounds and Treatments

A Groundbreaking New Approach to Treating Chronic Abdominal Pain

Researchers at the University of Vienna develop gut-stable oxytocin analogues for targeted pain treatment of chronic abdominal pain

Photo by Andrea Piacquadio on Pexels

A research team at the University of Vienna, led by medicinal chemist Markus Muttenthaler, has developed a new class of oral peptide therapeutic leads for treating chronic abdominal pain. This groundbreaking innovation offers a safe, non-opioid-based solution for conditions such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD), which affect millions of people worldwide. The research results were published in Angewandte Chemie.

An innovative approach to pain management

Current medications used to treat chronic abdominal pain often rely on opioids. However, opioids can cause severe side effects such as addiction, nausea, and constipation. Additionally, they affect the central nervous system, often leading to fatigue and drowsiness, which impairs the quality of life of those affected. The addiction risk is particularly problematic and has contributed to the ongoing global opioid crisis. Therefore, there is an urgent need for alternatives that minimise these risks.

This new therapeutic approach targets oxytocin receptors in the gut, which, in addition to its role in social bonding, also affects pain perception. When the peptide hormone oxytocin binds to these receptors, it triggers a signal that reduces pain signals in the gut. The advantage of this approach is that the effect is gut-specific, thus having a lower risk of side effects due to its non-systemic, gut-restricted action.

Oxytocin itself cannot be taken orally because it is rapidly broken down in the gastrointestinal tract. However, Prof Muttenthaler’s team has successfully created oxytocin compounds that are fully gut-stable yet can still potently and selectively activate the oxytocin receptor. This means these newly developed oxytocin-like peptides can be taken orally, allowing for convenient treatment for patients. This approach is especially innovative since most peptide drugs (such as insulin, GLP1 analogues) need to be injected as they are also quickly degraded in the gut.

“Our research highlights the therapeutic potential of gut-specific peptides and offers a new, safe alternative to existing pain medications, particularly for those suffering from chronic gut disorders and abdominal pain,” explains Muttenthaler.

Next steps and future outlook

With support from the European Research Council, the scientists are now working to translate their research findings into practice. The goal is to bring these new peptides to market as an effective and safe treatment for chronic abdominal pain. Moreover, the general approach of oral, stable, and gut-specific peptide therapeutics could revolutionise the treatment of gastrointestinal diseases, as the therapeutic potential of peptides in this area has not yet been fully explored.

The team has already secured a patent for the developed drug leads and is now actively seeking investors and industrial partners to advance the drug leads towards the clinic.

Source: University of Vienna

New Anti-cancer Agent Works Without Oxygen

Human colon cancer cells. Credit: National Cancer Institute

Tumours often contain areas of oxygen-deficient tissue that frequently withstand conventional therapies. This is because the drugs applied in tumours require oxygen to be effective. An international research team has developed a novel mechanism of action that works without oxygen: polymeric incorporated nanocatalysts target the tumour tissue selectively and switch off the glutathione that the cells need to survive. The team published their findings in the journal Nature Communications.

Why tumours shrink but don’t disappear

Study leader Dr Johannes Karges from Ruhr University Bochum, Germany, explained: “As tumours grow very quickly, consume a lot of oxygen and their vascular growth can’t necessarily keep pace, they often contain areas that are poorly supplied with oxygen.” These areas, often in the centre of the tumour, frequently survive treatment with conventional drugs, so that the tumour initially shrinks but doesn’t disappear completely. This is because the therapeutic agents require oxygen to be effective. 

The mechanism of action developed by Karges’ team works without oxygen. “It’s a catalyst based on the element ruthenium, which oxidises the naturally present glutathione in the cancer cells and switches it off,” explains Karges. Glutathione is essential for the survival of cells and protects them from a wide range of different factors. If it ceases to be effective, the cell deteriorates. 

Compound accumulates in tumour tissue

All cells of the body need and contain glutathione. However, the catalyst has a selective effect on cancer cells as it is packaged in polymeric nanoparticles that accumulate specifically in the tumour tissue. Experiments on cancer cells and on mice with human tumours, that were considered incurable, proved successful. “These are encouraging results that need to be confirmed in further studies,” concludes Johannes Karges. “Still, there’s a lot of research work to be done before it can be used in humans.”

Source: Ruhr-University Bochum

Crop-destroying Fungus Yields a Potential Colorectal Cancer Treatment

Plant fungus provides new drug with a new cellular target

Human colon cancer cells. Credit: National Cancer Institute

Novel chemical compounds from a fungus could provide new perspectives for treating colorectal cancer, one of the most common and deadliest cancers worldwide. The fungus, Bipolaris victoriae, is otherwise known as a fungal plant pathogen which in the 1940s caused the “Victoria blight”, decimating oats and similar grains in the US.

In the journal Angewandte Chemie, researchers reported on the isolation and characterisation of a previously unknown class of metabolites (terpene-nonadride heterodimers). One of these compounds effectively kills colorectal cancer cells by attacking the enzyme DCTPP1, which thus may serve as a potential biomarker for colorectal cancer and a therapeutic target.

Rather than using conventional cytostatic drugs, which have many side effects, modern cancer treatment frequently involves targeted tumour therapies directed at specific target molecules in the tumour cells. The prognosis for colorectal cancer patients remains grim however, demanding new targets and novel drugs.

Targeted tumour therapies are mostly based on small molecules from plants, fungi, bacteria, and marine organisms. About half of current cancer medications were developed from natural substances. A team led by Ninghua Tan, Yi Ma, and Zhe Wang at the China Pharmaceutical University (Nanjing, China) chose to use Bipolaris victoriae S27, a fungus that lives on plants, as the starting point in their search for new drugs.

The team first analysed metabolic products by cultivating the fungus under many different conditions (OSMAC method, one strain, many compounds). They discovered twelve unusual chemical structures belonging to a previously unknown class of compounds: terpene-nonadride heterodimers, molecules made from one terpene and one nonadride unit. Widely found in nature, terpenes are a large group of compounds with very varied carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings with maleic anhydride groups. The monomers making up this class of dimers termed “bipoterprides” were also identified and were found to contain additional structural novelties (bicyclic 5/6-nonadrides with carbon rearrangements).

Nine of the bipoterprides were effective against colorectal cancer cells. The most effective was bipoterpride No. 2, which killed tumour cells as effectively as the classic cytostatic drug Cisplatin. In mouse models, it caused tumours to shrink with no toxic side effects.

The team used a variety of methods to analyse the drug’s mechanism: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme that regulates the cellular nucleotide pool. The heterodimer binds significantly more tightly than each of its individual monomers. The activity of DCTPP1 is elevated in certain types of tumours, promoting the invasion, migration, and proliferation of the cancer cells while also inhibiting programmed cell death. It can also help cancer cells to resist treatment. Bipoterpride 2 inhibits this enzymatic activity and disrupts the now pathologically altered amino acid metabolism in the tumour cells.

The team was thus able to identify DCTPP1 as a new target for the treatment of colorectal cancer and bipoterprides as new potential drug candidates.

Source: Wiley

“Two for the Price of One” – New Process that Drives Anti-viral Immunity is Discovered

Scientists at Trinity College Dublin have discovered a new process in the immune system that leads to the production of an important family of anti-viral proteins called interferons. They hope the discovery will now lead to new, effective therapies for people with some autoimmune and infectious diseases.

Reporting in Nature Metabolism, Luke O’Neill, Professor of Biochemistry in the School of Biochemistry and Immunology at Trinity, and his team have found that a natural metabolite called Itaconate can stimulate immune cells to make interferons by blocking an enzyme called SDH. 

Co-lead author, Shane O’Carroll, from Trinity’s School of Biochemistry and Immunology, said: “We have linked the enzyme SDH to the production of interferons in an immune cell type called the macrophage. We hope our work will help the effort to develop better strategies to fight viruses because interferons are major players in how our innate immune system eliminates viruses – including COVID-19.” 

Co-lead author, Christian Peace, from Trinity’s School of Biochemistry and Immunology, added: “Itaconate is a fascinating molecule made by macrophages during infections. It’s already known to suppress damaging inflammation but now we have found how it promotes anti-viral interferons.”

Working with drug companies Eli Lilly and Sitryx Ltd, the next step is to test new therapies  based on Itaconate in various diseases, with some autoimmune diseases and some infectious diseases on the likely list. And the work potentially extends to other disease contexts in which SDH is inhibited, such as cancer, and could reveal a new therapeutic target for SDH-deficient tumours.

Prof O’Neill said: “With Itaconate you get two for the price of one – not only can it block harmful inflammation, but it can also help fight infections. We have discovered important mechanisms for both and the hope now is that patients will benefit from new therapies that exploit Itaconate and its impacts.” 

Clinical trials in patients are set to start next year.  

Source: Trinity College Dublin

Novel Glass-based Bone Cancer Therapy has a 99% Success Rate

Photo by National Cancer Institute on Unsplash

Bioactive glasses, a filling material which can bond to tissue and improve the strength of bones and teeth, has been combined with gallium to create a potential treatment for bone cancer. Tests in labs have found that bioactive glasses doped with the metal have a 99% success rate of eliminating cancerous cells and can even regenerate diseased bones.

The research was conducted by a team of Aston University scientists led by Professor Richard Martin at the College of Engineering and Physical Sciences.

In laboratory tests 99% of osteosarcoma (bone cancer) cells were killed off without destroying non-cancerous normal human bone cells. The researchers also incubated the bioactive glasses in a simulated body fluid and after seven days they detected the early stages of bone formation. 

Gallium is highly toxic, and the researchers found that the ‘greedy’ cancer cells soak it up and self-kill, which prevented the healthy cells from being affected. Their research appears in the journal Biomedical Materials.

Osteosarcoma is the mostly commonly occurring primary bone cancer and despite the use of chemotherapy and surgery to remove tumours survival rates have not improved much since the 1970s. Survival rates are dramatically reduced for patients who have a recurrence and primary bone cancer patients are more susceptible to bone fractures. 

Despite extensive research on different types of bioactive glass or ceramics for bone tissue engineering, there is limited research on targeted and controlled release of anti-cancer agents to treat bone cancers.

Professor Martin said: “There is an urgent need for improved treatment options and our experiments show significant potential for use in bone cancer applications as part of a multimodal treatment.

“We believe that our findings could lead to a treatment that is more effective and localised, reducing side effects, and can even regenerate diseased bones.

“When we observed the glasses, we could see the formation of a layer of amorphous calcium phosphate/ hydroxy apatite layer on the surface of the bioactive glass particulates, which indicates bone growth.”
The glasses were created in the Aston University labs by rapidly cooling very high temperature molten liquids (1450°C) to form glass. The glasses were then ground and sieved into tiny particles which can then be used for treatment.  

In previous research the team achieved a 50% success rate but although impressive, this was not enough to be a potential treatment. The team are now hoping to attract more research funding to conduct trials using gallium.

Dr Lucas Souza, research laboratory manager for the Dubrowsky Regenerative Medicine Laboratory at the Royal Orthopaedic Hospital, Birmingham worked on the research with Professor Martin. He added: “The safety and effectiveness of these biomaterials will need to be tested further, but the initial results are really promising.

“Treatments for a bone cancer diagnosis remain very limited and there’s still much we don’t understand. Research like this is vital to support in the development of new drugs and new methodologies for treatment options.”

Source: Aston University

Self-medicating Gorillas and Traditional Healers Provide Clues for New Drug Discovery

Four plants eaten by gorillas, also used in Gabonese traditional medicine, have antibacterial effects

Four plants consumed by wild gorillas in Gabon and used by local communities in traditional medicine show antibacterial and antioxidant properties, find Leresche Even Doneilly Oyaba Yinda from the Interdisciplinary Medical Research Center of Franceville in Gabon and colleagues in a new study publishing September 11 in the open-access journal PLOS ONE.

Wild great apes often consume medicinal plants that can treat their ailments. The same plants are often used by local people in traditional medicine.

To investigate, researchers observed the behavior of western lowland gorillas (Gorilla gorilla gorilla) in Moukalaba-Doudou National Park in Gabon and recorded the plants they ate. Next, they interviewed 27 people living in the nearby village of Doussala, including traditional healers and herbalists, about the plants that were used in local traditional medicine. The team identified four native plant species that are both consumed by gorillas and used in traditional medicine: the fromager tree (Ceiba pentandra), giant yellow mulberry (Myrianthus arboreus), African teak (Milicia excelsa) and fig trees (Ficus). They tested bark samples of each plant for antibacterial and antioxidant properties and investigated their chemical composition.

The researchers found that the bark of all four plants had antibacterial activity against at least one multidrug-resistant strain of the bacterium Escherichia coli. The fromager tree showed “remarkable activity” against all tested E. coli strains. All four plants contained compounds that have medicinal effects, including phenols, alkaloids, flavonoids, and proanthocyanidins. However, it’s not clear if gorillas consume these plants for medicinal or other reasons.

Biodiverse regions, such as central Africa, are home to a huge reservoir of unexplored and potentially medicinal plants. This research provides preliminary insights about plants with antibacterial and antimicrobial properties, and the four plants investigated in this study might be promising targets for further drug discovery research – particularly with the aim of treating multidrug-resistant bacterial infections.

The authors add: “Alternative medicines and therapies offer definite hope for the resolution of many present and future public health problems. Zoopharmacognosy is one of these new approaches, aimed at discovering new drugs.”

Provided by PLOS

Snake Antivenom Mired by Shortages and Side-effects – Could a New Treatment Boost Our Options?

By Jesse Copelyn

The only effective treatment for severe snakebite envenomation from a potentially deadly snake is antivenom. (Picture: Johan Marais, African Snakebite Institute)

In recent years, shortages of snake antivenom have plagued South Africa and much of the globe. Even when antivenom is available, potentially serious side effects often limit its use. Jesse Copelyn unpacks the fascinating details behind the antivenom products that might save your life and takes a look at a promising experimental treatment.

Every day, somewhere between 220 and 380 people die from snakebite around the world, yet according to Doctors Without Borders (MSF) the problem remains “chronically underfunded and neglected”.

MSF’s senior advisor on neglected tropical diseases, Koert Ritmeijer, tells Spotlight that in 2019 the World Health Organization (WHO) committed to halve the number of snakebite deaths by 2030. But this hasn’t been followed by any significant support from donor countries or philanthropic foundations, he says, with programmes that aim to “increase patients’ access to antivenoms [remaining] very underfunded”.

Antivenom is the primary registered class of treatments for snakebite. Long-running global shortages of the treatment continue to leave patients in poorer parts of the world without the care they need. That’s in part because pharmaceutical companies haven’t always found it profitable to produce. The treatment takes a long time to manufacture and it has to be geared to a specific or small group of snake species. The clientele are often those that are least able to pay, namely Africa and Asia’s rural poor.

With a limited number of suppliers, and thus a lack of market competition, prices remain high, making it difficult for many African governments to import antivenom without donor assistance.

South Africa has long been an exception. It’s the only country in Sub-Saharan Africa that produces its own antivenom – which is internationally recognised and outperforms several comparable products when studied in mice. Additionally, research done in the Western Cape shows that hospital pharmacies have traditionally had stock on hand.

However, last year production delays at the country’s state-run manufacturer, the South African Vaccine Producers (SAVP), led to a nation-wide shortage of antivenom, leaving many snakebite victims with limited options. The locally made SAVP products (previously the SAIMR) have historically been the main source of antivenom in the country.

While the nation-wide stockouts were reportedly resolved within a few months, this appears to have been more than a one-time blip. Even before the national shortage made news headlines last year, neighbouring countries that rely on South African antivenom were struggling to procure enough of the product. For instance, a 2022 study states that supply to Eswatini was becoming “increasingly and disturbingly intermittent” and that a charitable foundation there had “been unable to secure a supply of this antivenom for several months”.

Meanwhile, CEO of the African Snakebite Institute, Johan Marais told Spotlight that vets in South Africa have been struggling to access sufficient supplies for the last three years (the same SAVP products that are used to treat humans are sometimes used on pet dogs that get bitten). He said stocks in the country were low heading into snakebite season – spring and summer.

Southern Africa has 176 different types of snakes. (Infograph: African Snakebite Institute)

Compounding the problem is that even at the best of times, people in poor rural areas often struggle to access antivenom shortly after being bitten (even though the issue can be extremely time-sensitive). That’s because patients can’t simply get the drug at a local pharmacy or out of their medicine cabinet. Instead, they need to wait until they arrive at an intensive care unit before doctors can assess whether they require the treatment – and if they do, it has to be administered intravenously under carefully monitored conditions.

This is because antivenom comes with a range of side-effects. For instance, research at a Kwazulu-Natal hospital found that over three in five patients had some adverse reaction to the antidote, with nearly half of all patients going into anaphylactic shock, a severe allergic reaction that causes a person’s blood pressure to drop and makes it difficult to breathe. Consequently, health workers need to be on standby with adrenaline.

People who get bitten in rural areas far away from large healthcare facilities are thus often left in a precarious position despite being most at risk.

But why do antivenom products have so many side-effects in the first place? And why are they so difficult and time-consuming to manufacture? The answer has to do with the archaic way that antivenom is made.

A life-saving drug made of ‘horse junk’

In South Africa, the SAVP, which is a subsidiary of the National Health Laboratory Services (NHLS), makes antivenom by injecting small amounts of snake venom into a horse, so that the animal’s immune system can learn to recognise and combat the toxins. This is done repeatedly over a period of nine months until the horse becomes hyperimmunised, meaning its body produces massive numbers of antibodies which target the venom.

NHLS spokesperson, Mzi Gcukumana, says that once this happens, the horse’s “plasma is collected” (this is the liquid part of blood that contains the antibodies), and is then “carefully filtered in a sterile environment”.

The result is an antivenom product which targets the snake species that was used on the horse in the first place. At present, the SAVP makes three antivenoms: one for boomslang bites, another which is used for the saw-scaled viper, and a third, which treats bites from 10 different snake species found across the country, including the puff adder and rinkhals (which are some of the most common culprits of snakebite in South Africa). This multi-species product, known as a polyvalent antivenom, is made by injecting the horse with venom from different snake species.

There’s nothing unusual about the SAVP’s method – it’s the way everyone has made commercial snake antivenoms since the late 19th century (in some countries sheep are used instead of horses) and while it’s effective, it is also well-understood why it often induces serious side-effects.

Dr Kurt Wibmer, a scientist who is researching a new snakebite treatment, explains that with antivenom “only 10 to 20 percent of the medicine you’re getting is specific to the venom, and the other 80% is junk horse protein that your body doesn’t [need].” The result is that by injecting antivenom “you’re putting a bunch of foreign substances into your body, that the body then recognises as ‘not you’, and it develops an immune response to that [which can sometimes be extreme]”.

To add to these problems, antivenom is expensive. According to price lists shared with Spotlight by staff at the Tygerberg Poison Information Centre, the SAVP’s polyvalent product is currently priced at R2 400 per vial, while the boomslang product is sold for R7 700. And since most of the vial is “junk horse protein”, snakebite victims require multiple hits to get enough of the active ingredient. This could be 6 vials or it could be over 20.

With a high price tag, a laborious production process, and a host of side-effects that prevent health workers from saving snakebite victims at primary healthcare facilities, new treatments are badly needed – either to replace traditional antivenom or to complement it. Fortunately, many are being designed to address exactly these problems.

Over a hundred years later, anti-inflammatory drug may expand treatment options

One promising treatment in development is a synthetic anti-inflammatory medicine called Varespladib. This drug was originally developed as a treatment for conditions like acute coronary syndrome. After these efforts were abandoned, scientists discovered that the product may be able to play a role in treating snakebite victims.

That’s because Varespladib works by inhibiting an enzyme called sPLA2. sPLA2 is a core component of the venom of roughly 95% of vipers and elapids (two prominent venomous snake families). In fact, the enzyme plays a key role in many of the most harmful effects of this venom, including its ability to damage body tissue, paralyse victims, and cause heavy bleeding.

It is early days. Until now, the only evidence that suggests that Varespladib can block these effects is from studies done on mice and in petri dishes. However, a phase 2 clinical trial on humans, which has yet to be published, was just completed in the United States and India. In this research, snakebite victims who arrived at hospitals were randomly split into two groups: one got the Varespladib alongside standard treatment (like antivenom), while the other group got a placebo, plus ordinary treatment.

The results from the trial are currently under peer-review, though preliminary findings have been presented at conferences. Dr Matthew R Lewin, a co-author of the study and founder of a public benefit company that is developing the drug, told Spotlight that it looked like Veraspladib may help snakebite patients if used immediately (and when used alongside traditional treatment): “In the [trial] we took patients as long as 10 hours [after they had been bitten]. Up to 5 hours, we saw promising outcomes [from those who got Varespladib]… after 5 hours, the benefit was not apparent with respect to the primary outcome of the study”.

Time will tell whether these results will be confirmed not only in the peer-review process, but also in larger clinical trials (the present study only aimed to enrol 94 participants). If successful, Varespladib could represent an important advance.

That’s because safety trials show that unlike antivenom, the synthetic drug does not appear to cause any major side-effects. It can also be taken in pill-form, rather than being injected. This means that while snakebite victims would still have to wait until they got to a hospital to take antivenom, they would at least have something which they could take right away. While the study only looked at the effects of varespladib in combination with antivenom, Lewin suggests that “it is reasonable to expect that there will be a range of salutary [health-giving] effects” from varespladib alone, since it blocks sPLA2. He notes, however, that more research is needed.

And Varespladib isn’t the only new treatment in development. Others include a chelating agent which targets a metal-based component of snake venom. Though the evidence for this is so far only from studies in mice.

Nonetheless, since our primary treatment option for snakebite remains similar to what it was over a century ago, researchers are hopeful that we might finally begin to take a few steps forward.

Note:  This is part 1 of a two-part Spotlight series on snakebite treatment in South Africa. In part 2 we will, among others, look at promising advances that may help reduce antivenom shortages.

Republished from Spotlight under a Creative Commons licence.

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Controlling Lipid Levels with Less Side Effects Possible with New Drug

Image Credit: Institute of Transformative Bio-Molecules (ITbM), Nagoya University

Researchers at Nagoya University in Japan have developed a new compound, ZTA-261, that binds to thyroid hormone receptor beta (THRβ). THRβ plays an important role in the regulation of lipid metabolism, which affects lipid levels in the blood. Mice administered the drug showed decreased lipid levels in the liver and blood, with fewer side effects in the liver, heart, and bones compared to existing compounds.  These findings, published in Communications Medicine, suggest that ZTA-261 is an effective treatment for lipid disorders such as dyslipidaemia.

Approximately one in ten people is classified as obese or overweight, often due to abnormalities in lipid metabolism. Abnormal levels of lipids in the blood, known as dyslipidaemia, lead to an increased risk of chest pain, heart attack, and stroke.

There is growing interest in developing treatments for dyslipidaemia that leverage the properties of thyroid hormones. Thyroid hormones increase overall metabolism through binding to two types of receptors: alpha (THRα) and beta (THRβ). The brain, heart, and muscle contain the α-subtype, whereas the liver and pituitary gland primarily express the β-subtype.

Treatments that rely on THR activation face challenges due to the side effects of thyroid hormones. Although THRα regulates cardiovascular functions, excess levels of thyroid hormone lead to adverse effects in nearby organs such as heart enlargement and muscle and bone wasting. On the other hand, activation of THRβ influences lipid metabolism without these severe side effects.

As a result, THRβ has become a desirable target for treating metabolic disorders such as dyslipidaemia. However, common treatments, such as the natural thyroid hormone T3, show almost no selectivity between the α and β receptors, making it difficult to avoid the severe side effects caused by binding to THRα.

To address this problem, a research team, including Masakazu Nambo, Taeko Ohkawa, Ayato Sato, Cathleen Crudden, and Takashi Yoshimura from Nagoya University’s WPI-ITbM, developed ZTA-261, a thyroid hormone derivative drug with a similar structure. To test its efficacy, they compared it with GC-1, another thyroid hormone derivative, and the natural thyroid hormone T3 in a mouse model.

They found that ZTA-261 had almost 100 times higher selectivity for THRβ than THRα. In comparison, GC-1 showed only a 20-fold difference in affinity, showing ZTA-261’s superior selectivity. This was confirmed by the significant increase in heart weight and bone damage indicators in T3-treated mice but not in those treated with ZTA-261.

“Our findings suggest that ZTA-261 is much less toxic than T3 and even less toxic than GC-1, which is known as a THRβ-selective compound,” Ohkawa said. “I find it amazing that the difference in THR beta-selectivity between ZTA-261 and GC-1 – 100 times selectivity versus 20 times selectivity – truly has this big an impact on heart and bone toxicity.”

As many drugs have been discontinued in preclinical trials because of their toxicity in the liver, the researchers checked for potential liver toxicity by measuring alanine aminotransferase (ALT) levels in the blood. Their findings confirmed the safety of the drug, finding no significant differences in ALT levels between mice treated with ZTA-261 and those treated with saline. Although these results are promising, more studies, including human trials, will be necessary before considering ZTA-261 for clinical use. However, this breakthrough represents a significant step forward in the development of safer treatments for lipid disorders.

“ZTA-261 has extremely high affinity and selectivity for THRβ among the thyroid hormone derivatives developed to date,” Nambo explained. “In the process of synthesising a variety of derivatives, we have found that precise molecular design is crucial for both selectivity and affinity. We believe that this study will provide new and important insights into drug discovery.”

Source: Institute of Transformative Bio-Molecules (ITbM), Nagoya Universityy

Repurposed Drug Combination Promising in the Treatment of Retinal Degenerations

Retina and nerve cells. Credit: NIH

An international team of researchers have tested a combination treatment incorporating three existing drugs and successfully slowed disease progression in pre-clinical retinopathy models. Their results, which used tamsulosin, metoprolol and bromocriptine are published in Nature Communications.

Drug repurposing refers to the use of existing drugs to treat diseases or conditions which they were not originally developed or approved for, and offer a strategy to treat rare diseases for which new drug development is too costly. The new study focused on drug repurposing in the context of inherited retinal degenerations, IRDs. IRDs are a group of genetic diseases that cause the deterioration of retinal anatomy and function, leading to gradual loss of vision and often blindness. Most IRDs are currently inaccessible therapeutically, comprising an unmet medical need for a substantial population worldwide.

A combination treatment incorporating three drugs slowed disease progression 

The researchers found that a combination treatment incorporating three drugs significantly slowed disease progression and decreased disease manifestation in four different animal models of IRD. The combination included the blood pressure and heart failure drug metoprolol, and tamsulosin, which is used for the treatment of benign prostatic hyperplasia, as well as the nowadays less commonly used Parkinson’s disease drug bromocriptine.

“In drug repurposing, it does not matter to which diseases or conditions the drugs were originally developed for, but it is the molecular-level effects of drugs, or pharmacology, that count,” says first author Dr Henri Leinonen, currently Adjunct Professor of Neuropharmacology at the University of Eastern Finland.

In retinal degenerations, intracellular secondary messengers such as cyclic adenosine monophosphate and calcium are believed to be overactive, exacerbating the disease. Metoprolol, tamsulosin and bromocriptine suppress the activity of these secondary messengers via their own distinct cell membrane-receptor actions.

“We hypothesised that the combined effect of these drugs would alleviate the disease, which it indeed did in several distinct animal models of IRDs. However, the efficacy and safety of this combination in humans with retinal degeneration is not guaranteed, and controlled clinical trials to test these are needed,” Dr Leinonen notes.

It is noteworthy that none of the drugs used in the study were effective against retinal degeneration on their own; instead, their combination was necessary for efficacy. According to Dr Leinonen, the same phenomenon may apply to many diseases that are currently untreatable, and especially in multifactorial diseases, effective treatment may require multiple drugs to be used simultaneously.

Drug repurposing could provide solutions especially for the treatment of rare diseases

Rare diseases, IRDs included, are seldom of major interest for the pharmaceutical industry due to a lack of economic incentives. But drug repurposing, actively researched in academia, is a promising method to find solutions for rare diseases that remain therapeutically inaccessible.

The most significant advantages of drug repurposing can be found in faster drug development times and lower costs. Since repurposed drugs have already undergone several mandatory safety tests and early stages of clinical trials, their market entry is considerably faster and cheaper than that of completely new drugs. Drug safety is also an important aspect, as the relative safety of repurposed drugs compared to a completely new chemical reduces risks and uncertainty, which is often considered the most critical point in the drug development process.

Source: University of Finland

Heparin Could be a New Cobra Venom Antidote

Cheap, available drug could help reduce impact of snakebites worldwide

Photo by Nivedh P on Unsplash

More than 100 000 people die from snake bites every year. Cobra antivenom is expensive and doesn’t treat the necrosis of flesh caused by the bite, which can lead to amputations. Now, Scientists at the University of Sydney and Liverpool School of Tropical Medicine have made a remarkable discovery: a commonly used blood thinner, heparin, can be repurposed as an inexpensive antidote for cobra venom.

“Our discovery could drastically reduce the terrible injuries from necrosis caused by cobra bites – and it might also slow the venom, which could improve survival rates,” said Professor Greg Neely, a corresponding author of the study from the University of Sydney.

Using CRISPR gene-editing technology to identify ways to block cobra venom, the team, which consisted of scientists based in Australia, Canada, Costa Rica and the UK, successfully repurposed heparin and related drugs and showed they can stop the necrosis caused by cobra bites.

The research is published on the front cover of Science Translational Medicine.

PhD student and lead author, Tian Du, also from the University of Sydney, said: “Heparin is inexpensive, ubiquitous and a World Health Organization-listed Essential Medicine. After successful human trials, it could be rolled out relatively quickly to become a cheap, safe and effective drug for treating cobra bites.”

The team used CRISPR to find the human genes that cobra venom needs to cause necrosis that kills the flesh around the bite. One of the required venom targets are enzymes needed to produce the related molecules heparan and heparin, which many human and animal cells produce. Heparan is on the cell surface and heparin is released during an immune response. Their similar structure means the venom can bind to both. The team used this knowledge to make an antidote that can stop necrosis in human cells and mice.

Unlike current antivenoms for cobra bites, which are 19th century technologies, the heparinoid drugs act as a ‘decoy’ antidote. By flooding the bite site with ‘decoy’ heparin sulfate or related heparinoid molecules, the antidote can bind to and neutralise the toxins within the venom that cause tissue damage.

Joint corresponding author, Professor Nicholas Casewell, Head of the Centre for Snakebite Research & Interventions at Liverpool School of Tropical Medicine, said: “Snakebites remain the deadliest of the neglected tropical diseases, with its burden landing overwhelmingly on rural communities in low- and middle-income countries.

“Our findings are exciting because current antivenoms are largely ineffective against severe local envenoming, which involves painful progressive swelling, blistering and/or tissue necrosis around the bite site. This can lead to loss of limb function, amputation and lifelong disability.”

Snakebites kill up to 138 000 people a year, with 400 000 more experiencing long-term consequences of the bite. While the number affected by cobras is unclear, in some parts of India and Africa, cobra species account for most snakebite incidents.

Working in the Dr John and Anne Chong Laboratory for Functional Genomics at the Charles Perkins Centre, Professor Neely’s team takes a systematic approach to finding drugs to treat deadly or painful venoms. It does this using CRISPR to identify the genetic targets used by a venom or toxin inside humans and other mammals. It then uses this knowledge to design ways to block this interaction and ideally protect people from the deadly actions of these venoms.

This approach was used to identify an antidote to box jellyfish venom by the team in 2019.

Source: University of Sydney