Category: New Compounds and Treatments

Categories : New Compounds and TreatmentsTags :

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

On By ModernMedia

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.

Read the original article

Categories : Metabolic Disorders New Compounds and TreatmentsTags :

Controlling Lipid Levels with Less Side Effects Possible with New Drug

On By ModernMedia
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

Categories : New Compounds and Treatments OphthalmologyTags :

Repurposed Drug Combination Promising in the Treatment of Retinal Degenerations

On By ModernMedia
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

Categories : New Compounds and TreatmentsTags :

Heparin Could be a New Cobra Venom Antidote

On By ModernMedia

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

Categories : Antibiotics New Compounds and TreatmentsTags :

New Antibiotic Kills Pathogenic Bacteria but Spares Healthy Gut Microbes

On By ModernMedia
Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers have developed a new antibiotic that reduced or eliminated drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis while sparing healthy microbes in the mouse gut. The drug, called lolamicin, also warded off secondary infections with Clostridioides difficile, and was effective against more than 130 multidrug-resistant bacterial strains in cell culture.

The findings are detailed in the journal Nature.

“People are starting to realise that the antibiotics we’ve all been taking – that are fighting infection and, in some instances, saving our lives – also are having these deleterious effects on us,” said University of Illinois Urbana-Champaign chemistry professor Paul Hergenrother, who led the study with former doctoral student Kristen Muñoz. “They’re killing our good bacteria as they treat the infection. We wanted to start thinking about the next generation of antibiotics that could be developed to kill the pathogenic bacteria and not the beneficial ones.”

“Most clinically approved antibiotics only kill gram-positive bacteria or kill both gram-positive and gram-negative bacteria,” Muñoz said.

The few drugs available to fight gram-negative bacteria, which are protected by their double cell walls, also kill other potentially beneficial gram-negative bacteria. For example, colistin, one of the few gram-negative-only antibiotics approved for clinical use, can cause C. difficile-associated diarrhoea and pseudomembranous colitis, a potentially life-threatening complication. The drug also has toxic effects on the liver and kidney, and “thus colistin is typically utilised only as an antibiotic of last resort,” the researchers wrote.

To tackle the many problems associated with indiscriminately targeting gram-negative bacteria, the team focused on a suite of drugs developed by the pharmaceutical company AstraZeneca. These drugs inhibit the Lol system, a lipoprotein-transport system that is exclusive to gram-negative bacteria and genetically different in pathogenic and beneficial microbes. These drugs were not effective against gram-negative infections unless the researchers first undermined key bacterial defenses in the laboratory. But because these antibiotics appeared to discriminate between beneficial and pathogenic gram-negative bacteria in cell culture experiments, they were promising candidates for further exploration, Hergenrother said.

In a series of experiments, Muñoz designed structural variations of the Lol inhibitors and evaluated their potential to fight gram-negative and gram-positive bacteria in cell culture. One of the new compounds, lolamicin, selectively targeted some “laboratory strains of gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae,” the researchers found. Lolamicin had no detectable effect on gram-positive bacteria in cell culture. At higher doses, lolamicin killed up to 90% of multidrug-resistant E. coli, K. pneumoniae and E. cloacae clinical isolates.

When given orally to mice with drug-resistant septicemia or pneumonia, lolamicin rescued 100% of the mice with septicemia and 70% of the mice with pneumonia, the team reported.

Extensive work was done to determine the effect of lolamicin on the gut microbiome.

“The mouse microbiome is a good tool for modeling human infections because human and mouse gut microbiomes are very similar,” Muñoz said. “Studies have shown that antibiotics that cause gut dysbiosis in mice have a similar effect in humans.”

Treatment with standard antibiotics amoxicillin and clindamycin caused dramatic shifts in the overall structure of bacterial populations in the mouse gut, diminishing the abundance several beneficial microbial groups, the team found.

“In contrast, lolamicin did not cause any drastic changes in taxonomic composition over the course of the three-day treatment or the following 28-day recovery,” the researchers wrote.

Many more years of research are needed to extend the findings, Hergenrother said. Lolamicin, or other similar compounds, must be tested against more bacterial strains and detailed toxicology studies must be conducted. Any new antibiotics also must be assessed to determine how quickly they induce drug resistance, a problem that arises sooner or later in bacteria treated with antibiotics.

The study is a proof-of-concept that antibiotics that kill a pathogenic microbe while sparing beneficial bacteria in the gut can be developed for gram-negative infections – some of the most challenging infections to treat, Hergenrother said.

Source: University of Illinois at Urbana-Champaign, News Bureau

Categories : Cancer New Compounds and TreatmentsTags :

New Treatment Quadruples 3-year Survival for Rare and Aggressive Cancer

On By ModernMedia
Photo by National Cancer Institute on Unsplash

An innovative treatment significantly increases the survival of people with malignant mesothelioma, a rare but rapidly fatal type of cancer with few effective treatment options, according to results from a clinical trial led by Queen Mary University of London and published in JAMA Oncology.

The phase 3 clinical trial, led by Professor Peter Szlosarek at Queen Mary and sponsored by Polaris Pharmaceuticals, has unveiled a breakthrough in the treatment of malignant pleural mesothelioma (MPM), a rare and often rapidly fatal form of cancer with limited therapeutic options.

The ATOMIC-meso trial, a randomised placebo-controlled study of 249 patients with MPM, found that a treatment – which combines a new drug, ADI-PEG20, with traditional chemotherapy – increased the median survival of participants by 1.6 months, and quadrupled the survival at 36 months, compared to placebo-chemotherapy.

The findings are significant, as MPM has one of the lowest 5-year survival rates of any solid cancer of around 5-10%. This innovative approach marks the first successful combination of chemotherapy with a drug that targets cancer’s metabolism developed for this disease in 20 years.

MPM is a rare, aggressive cancer that affects the lining of the lungs and is associated with exposure to asbestos. It’s usually treated with potent chemotherapy drugs, but these are seldom able to halt the progression of the disease.

The premise behind this new drug treatment is elegant in its simplicity – starving the tumour by cutting off its food supply. All cells need nutrients to grow and multiply, including amino acids like arginine. ADI-PEG20 works by depleting arginine levels in the bloodstream. For tumour cells that can’t manufacture their arginine due to a missing enzyme, this means their growth is thwarted.

The ATOMIC-meso trial is the culmination of 20 years of research at Queen Mary’s Barts Cancer Institute that began with Professor Szlosarek’s discovery that malignant mesothelioma cells lack a protein called ASS1, which enables cells to manufacture their own arginine. He and his team have since dedicated their efforts to using this knowledge to create an effective treatment for patients with MPM.

Professor Szlosarek said: “It’s truly wonderful to see the research into the arginine starvation of cancer cells come to fruition. This discovery is something I have been driving from its earliest stages in the lab, with a new treatment, ADI-PEG20, now improving patient lives affected by mesothelioma. I thank all the patients and families, investigators and their teams, and Polaris Pharmaceuticals for their commitment to defining a new cancer therapy.”

There are ongoing studies assessing ADI-PEG20 in patients who have sarcoma or glioblastoma multiforme and other cancers dependent on arginine. The success of this novel chemotherapy in MPM also suggests that the drug may be of benefit in the treatment of multiple other types of cancer. 

Source: Queen Mary University London

Categories : Cancer New Compounds and TreatmentsTags :

Dual Immunotherapy Drugs Show Promise vs a Range of Advanced Cancers

On By ModernMedia
Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

In an early phase clinical trial, a combination of antibody-based medications targeting the immune system generated promising safety data and anti-tumour activity in individuals with various types of advanced cancer. The findings appear online in CANCER, a peer-reviewed journal of the American Cancer Society.

Both medications tested in the trial are checkpoint inhibitors, and support immune responses against tumour cells. CS1002 increases the activation and proliferation of T immune cells by binding to a T cell receptor called CTLA-4. CS1003, also called nofazinlimab, blocks the programmed cell death protein 1 that is expressed on various types of immune cells and plays a role in suppressing the immune system.

In this first-in-human multicentre, open-label study conducted from April 26, 2018 to January 18, 2022 at 9 study sites in Australia and China, phase Ia involved monotherapy dose-escalation (Part 1), which was followed by phase Ib combination therapy dose escalation (Part 2) and expansion (Part 3). Various dosing schedules of CS1002 (0.3, 1, or 3mg/kg once every three weeks, or 3mg/kg once every 9 weeks) were evaluated with 200mg CS1003 once every three weeks.

Parts 1, 2, and 3 of the trial included 13, 18, and 61 patients, respectively, who had advanced/metastatic solid, relapsed, or refractory tumors. During treatment, investigators did not observe any dose-limiting toxicities or a maximum tolerated dose. Treatment-related side effects such as diarrhoea, fatigue, and rash were reported in 30.8%, 83.3%, and 75.0% of patients in Parts 1, 2, and 3, respectively. Serious side effects such as intestinal inflammation and severe skin reactions were experienced by 15.4%, 50.0%, and 18.3% of patients in each part.

Of 61 patients evaluable for treatment efficacy, 23 (37.7%) with different types of tumours experienced a positive response. Higher response rates occurred with conventional and high-dose CS1002 regimens (1mg/kg once every three weeks or 3mg/kg once every 9 weeks) compared with low-dose CS1002 (0.3mg/kg once every three weeks) in certain cancers such as melanoma and skin cancer.

“CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising anti-tumor activities across CS1002 dose levels when combined with CS1003,” the investigators wrote. They concluded that this warranted more testing of CS1002 in combination with CS1003 for the treatment of solid tumours.

Source: Wiley

Categories : New Compounds and TreatmentsTags :

Abatacept may Hold Back Progression of Rheumatoid Arthritis

On By ModernMedia
Photo by Towfiqu barbhuiya

Results from a Phase 2b clinical trial, published in The Lancet, provides hope for arthritis sufferers after it was shown that the biologic drug abatacept reduces progression to this agonising chronic inflammatory disease.

Rheumatoid arthritis is an autoimmune condition that typically (but not always) starts in middle age, with joint pain, swelling and significant disability. Until now there is no cure or prevention.

Abatacept is currently used as an effective second or third line treatment for people living with established rheumatoid arthritis and is given by weekly injections at home or intravenously in hospital.

Researchers from King’s College London recruited 213 patients at high risk of the disease to understand whether a year-long treatment of the biologic drug could be used to prevent progression to rheumatoid arthritis.

They recruited men and women over the age of 18 with early symptoms such as joint pain but no joint swelling, and treated half with the drug and half with a placebo every week for a year. The study drug was then stopped, and study participants monitored for a further 12 months.

After twelve months of treatment, 6% of patients treated with abatacept had developed arthritis compared to 29% in the placebo arm. By 24 months, the differences were still significant, with a total of 25% progressing to rheumatoid arthritis in the abatacept arm compared to 37% in the placebo arm.

Secondary outcomes for the trial showed that abatacept was associated with improvements in pain scores, function and quality of life measurements, as well as lower scores of inflammation of the lining of joints detectable by ultrasound scan.

Professor Andrew Cope, Professor of Rheumatology from School of Immunology & Microbial Sciences, said: “This is the largest rheumatoid arthritis prevention trial to date and the first to show that a therapy licensed for use in treating established rheumatoid arthritis is also effective in preventing the onset of disease in people at risk.

“These initial results could be good news for people at risk of arthritis as we show that the drug not only prevents disease onset during the treatment phase but can also ease symptoms such as pain and fatigue. This is also promising news for the NHS as the disease affects people as they age and will become more expensive to treat with a growing aging population.”

Philip Day, a 35-year-old software engineer and founder of FootballMatcher from Eltham, was at high-risk for rheumatoid arthritis. A keen football player, Philip’s joint pain deterred him from playing and affected his day-to-day life. He was enrolled in the trial in 2018, at the age of the 30, and was prescribed abatacept.

He said: “The pain got so terrible I stopped going to football, and I got lazier and felt progressively worse physically and mentally. The pain was unpredictable, it would show up in my knees one day, my elbows the next, and then my wrists or even my neck. At the time, my wife and I wanted to have children and I realised my future was pretty bleak if the disease progressed. I’d always wanted to be the kind of dad that played football with his son and I knew the pain would stop me from realising that dream.

“Enrolling in the trial was a no-brainer; it was a ray of hope at a dark time. Within a few months I had no more aches or pains and five years on I’d say I’ve been cured. Now, I can play football with my three-year-old son and have a normal life.”

One year’s treatment with abatacept costs the NHS about £10 000 (ZAR 238 000) per patient. Side effects include upper respiratory tract infections, dizziness, nausea and diarrhoea, but these are generally mild.

Professor Cope added: “There are currently no drugs available that prevent this potentially crippling disease. Our next steps are to understand people at risk in more detail so that we can be absolutely sure that those at highest risk of developing rheumatoid arthritis receive the drug.”

Source:

Categories : Cancer New Compounds and TreatmentsTags :

Destroying Tumour Cells with Calcium

On By ModernMedia
Colourised scanning electron micrograph of a breast cancer cell. Credit: NIH

Calcium ions are essential for cells, but can be toxic in higher concentrations. A team of researchers has now designed and prepared a combination drug that kills tumour cells by modulating the calcium influx into the cell. An external calcium source is not necessary because only the calcium ions already present in the tumour tissue are used, according to the study published in the journal Angewandte Chemie.

Biological cells need calcium ions, among other things, for the proper functioning of the mitochondria, the powerhouses of the cells.

However, if there is too much calcium, the mitochondrial processes become unbalanced and the cell suffocates.

A research group led by Juyoung Yoon of Ewha Womens University in Seoul, South Korea, together with teams from China, has now taken advantage of this process and developed a synergistic antitumour drug that can open calcium channels and thus trigger a deadly calcium storm inside the tumour cell.

The researchers targeted two channels, the first one in the outer membrane, and the other was a calcium channel in the endoplasmic reticulum, a cell organelle that also stores calcium ions.

The channel located in the outer membrane opens when it is exposed to a large amount of reactive oxygen species (ROS), while the channel in the endoplasmic reticulum is activated by nitric oxide molecules.

To generate the ROS that open the outer membrane calcium channel, the researchers used the dye indocyanine green.

This bioactive agent can be activated by irradiation with near-infrared light, which not only triggers reactions that lead to ROS, but it also heats up the environment.

The team explains that the high local temperature activates the other active agent, BNN-6, to release nitric oxide molecules that open the channel in the endoplasmic reticulum.

Following successful trials in tumour cell lines, the team tested an injectable formulation in tumour-implanted mice.

To create a biocompatible combined drug, the researchers loaded the active ingredients into tiny modified porous silica beads that are not harmful to the body, but can be recognized by tumour cells and transported into the cell.

After injecting the beads into the bloodstream of the mice, the researchers observed that the drug accumulated in the tumour.

Exposure to near-infrared light successfully triggered the mechanism of action, and the tumour disappeared after a few days in mice that received the preparation.

The authors emphasise that this ion influx approach may also be useful in related biomedical research areas where a similar mechanism could activate ion channels different from calcium in order to find new therapeutic approaches.

Source: Wiley

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

New Drug with a Different Approach Holds Promise as a Treatment for Multiple Sclerosis

On By ModernMedia
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Researchers have found in pre-clinical studies of a small molecule drug that it has promise as a potential new treatment for multiple sclerosis (MS). The results from the Centre for Addiction and Mental Health-led study have been published in the journal Science Advances.

Expanding on Dr Fang Liu’s earlier work that identified a novel drug target for the treatment of MS, she and her team have now created a small molecule compound that is effective in two different animal models of MS. This represents a key advancement that brings this MS research closer to the clinic to impact patient care.

MS is a progressive neurological disease that currently has no cure.

It is associated with a wide-range of debilitating symptoms, including problems with coordination, cognition, muscle weakness and depression. For unknown reasons, it is more common in northern latitudes and more than twice as common in women.

It is known that MS damages myelin, a protective sheath that forms around nerves in the brain and spinal cord. As the myelin damage is triggered by inflammation in the immune system, up until now all current drug treatments for MS target the immune system.

In this study, CAMH Senior Scientist Dr Fang Liu and her team treated MS in a completely different way – targeting the glutamate system. Study results showed that the newly synthesised lead compound not only reduced MS-like symptoms, it also may repair the damaged myelin in two different pre-clinical models of MS.

“Our compound had a stunning effect on rescuing myelin and motor function in the lab models, and I hope these effects will translate to the clinic to add to current treatments and bring new hope to patients with MS,” said Dr Liu.

“As with cancer chemotherapy drug cocktails, simultaneous targeting of the MS disease pathway at multiple points can have synergistic effects and result in better outcomes.”

Dr Iain Greig, Reader in Medicinal Chemistry at the University of Aberdeen, alongside his team, are working to turn the molecules identified by Dr Liu into advanced “drug-like” molecules suitable for continued development towards clinical use in patients.

He added: “In all my years as a medicinal chemist, I have never seen a more promising starting point for a drug development project. It has been a huge pleasure to be involved in this program and I am looking forward to continuing to drive it towards to the clinic.”

Much of the funding for this novel treatment for MS, which Dr. Fang and her team have been investigating for over a decade, has come from the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society USA’s Fast Forward commercial research program.

“We are pleased to have helped enable the early development of a novel neuroprotective strategy for MS, and look forward to seeing it progress through the critical next stages needed to determine its potential benefits for people living with MS,” said Walt Kostich, PhD, head of the National MS Society (USA)’s Fast Forward commercial research programme.

Dr. Liu believes that the evidence of efficacy and tolerability generated in this study for the small molecule drug makes it a good candidate to be developed for human trials. The next steps in drug development will involve some further pre-clinical research, including investigating safety and stability of the compound. CAMH and the University of Aberdeen have already filed patent applications to protect this research and are actively seeking industry partners to further advance this work towards clinical trials over the next few years.

Source: Centre for Addiction and Mental Health