Reducing target systolic blood pressure lowers risk of cardiovascular disease and mortality

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A new study conducted by researchers from Tulane University finds reducing target systolic blood pressure below current recommendations significantly reduces the risk of cardiovascular disease and preventable death.

The latest study supports previous research, which found more intensive management of hypertension greatly reduced the risk of heart attack and stroke. The results of the latest study are published in JAMA Cardiology.

Hypertension is the leading preventable risk factor for cardiovascular disease and death. Current guidelines call for adults with hypertension to lower their systolic blood pressure to less than 140 mm Hg. Researchers from Tulane University School of Public Health and Tropical Medicine and Tulane School of Medicine analyzed 42 clinical trials involving more than 144,000 patients. They found significant linear associations between systolic blood pressure and risk of cardiovascular disease and mortality, with the lowest risk at a systolic blood pressure of 120 to 124 mm Hg.

“These findings support more intensive systolic blood pressure control among adults with hypertension,” says Jiang He, Joseph S. Copes chair and professor in the Department of Epidemiology at Tulane University School of Public Health and Tropical Medicine. “They suggest the need for revising the current clinical guidelines for management of high blood pressure.”

He says future clinical trials are needed to study the effects of intensive blood pressure reduction on chronic kidney disease and dementia. In addition, clinical trials of intensive blood pressure management among patients with diabetes and ischemic stroke are needed.


Repeated exposure to anesthesia early in life impairs visual recognition memory

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Repeated exposure to a common anesthesia drug early in life results in visual recognition memory impairment, which emerges after the first year of life and may persist long-term, according to a study from the Icahn School of Medicine at Mount Sinai and published online May 31 in the British Journal of Anaesthesia.

Each year, approximately a million children under the age of four undergo surgery with general anesthesia, according to the U.S. Food and Drug Administration (FDA). Experimental studies in animals have shown that exposure to general anesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function. Some human epidemiological studies have shown that children who undergo more than one operation under general anesthesia before they are four years old are at a greater risk of learning disability and other cognitive impairments.

The Mount Sinai study is among the first to address the question of whether repeated postnatal anesthesia exposure, in and of itself, results in memory impairment in a highly translationally relevant rhesus monkey model. Rhesus monkeys at birth are at a stage of neurodevelopment that is more similar to that of human infants than are neonatal rodents; with respect to brain growth, a six-week-old rhesus monkey corresponds to a human 6 to 12 months of age. Because these kinds of controlled studies cannot be carried out in humans, it is essential to use a comparable animal model to discover if anesthesia is affecting the brain. Unlike previous research, the study was conducted in the absence of a surgical procedure, co-morbidities that may necessitate surgical intervention, or the psychological stress associated with illness.

“The major strength of this study is its ability to separate anesthesia exposure from surgical procedures, which is a potential complication in the studies conducted in children,” says Mark Baxter, PhD, professor in the Departments of Neuroscience and Anesthesiology at the Icahn School of Medicine at Mount Sinai. “Our results confirm that multiple anesthesia exposures alone result in memory impairment in a highly translational animal model. Interestingly, the anesthesia-exposed group had normal visual memory at six months of age. Visual memory impairment didn’t emerge until the second year of life, corresponding roughly to the age of three to six years old in humans.”

Specifically, the study team exposed 10 non-human primate subjects to a common pediatric anesthetic called sevoflurane for four hours, the length of time required for a significant surgical procedure in humans. They were exposed to the anesthetic at postnatal day 7 and then again two and four weeks later, because human data indicate that repeated anesthesia results in a greater risk of cognitive disability relative to a single anesthetic exposure.

Researchers evaluated the visual recognition memory of exposed subjects compared with that of healthy controls at 6-10 months of age, 12-18 months of age and again at 24-30 months of age using the visual paired comparison test, which measures memory by assessing preference for looking at a new image over a previously viewed one. They found the anesthesia-exposed infants displayed no memory impairment when tested at 6-10 months, but demonstrated significant memory impairment (reduced time looking at the novel image) after the first year of life compared with the control group.

“Our findings are consistent with epidemiological studies that show increased risk of long-term cognitive impairments after repeated exposure to anesthesia in infancy and early childhood, but perhaps most interestingly, we found that these deficits may emerge at later developmental stages, even when memory performance is unaffected earlier in development,” says Dr. Baxter. “Our goal is to continue this work to test possible interventions that can prevent long-term cognitive impairments after early anesthesia exposure.”

These findings are part of a larger longitudinal study, and researchers at the Icahn School of Medicine at Mount Sinai and the Yerkes National Primate Research Center will continue to follow these study subjects behaviorally to fully characterize the length of time that cognitive and emotional changes persist and whether they resolve over time.

In December 2016, the FDA placed a warning on common anesthetic/sedative drugs, including sevoflurane, for children under three years of age receiving prolonged (more than three hours) or repeated anesthesia, saying that this may cause a risk of cognitive impairment.

This primate model may be used be researchers for future studies to develop a new anesthetic agent or prophylactic treatment to counteract the impact of anesthesia on behavior in children. The findings also suggest that additional work is required to identify the mechanisms by which anesthetics may cause long-term changes in central nervous system function that impact behavior.


Scientists report discovery and validation of drug candidate for treating cryptosporidiosis

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Infectious disease scientists from Novartis, the University of Georgia and Washington State University have reported the discovery and early validation of a drug candidate for treating cryptosporidiosis, a diarrheal disease which is a major cause of child mortality in lower-income countries.

Currently there are no vaccines or effective treatments.

“There’s a lot of uncertainty when embarking on drug discovery for a notoriously intractable parasite such as Cryptosporidium, the cause of cryptosporidiosis,” said Thierry Diagana, Head of the Novartis Institute for Tropical Diseases (NITD). “Thanks to the commitment of our funding collaborators and urgent action of our academic colleagues, we’ve made an important step toward advancing a new treatment.”

Diarrheal diseases cause more than 800,000 deaths annually. Epidemiological studies have highlighted the vital need for new treatment options against the protozoan parasite Cryptosporidium, which often infects its victims from exposure to contaminated water supplies. Nitazoxanide, the only approved treatment for cryptosporidiosis, has shown poor results in vulnerable infants and immune-compromised patients.

Yet there are obstacles to finding new treatments. The parasite perishes relatively quickly in labs and scientists have lacked research tools to identify drug candidates. The team developed a novel drug discovery process using transgenic parasites and novel disease models, leading to the identification and validation of the Cryptosporidium PI(4)K inhibitor candidate KDU731. They reported the discovery and preclinical findings in a recent issue of Nature.

Novartis is advancing research of cryptosporidiosis through collaborations with the global health community and its scientists at NITD, which is ramping up its research and operations in Emeryville, CA.


GlaxoSmithKline and AstraZeneca among drug stocks buoyed by Trump’s healthcare plans

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The Republicans are looking to repeal Obamacare as well as trying to ease regulatory pressures in the industry.

Shares in UK drugs giants GlaxoSmithKline plc (LON:GSK), AstraZeneca PLC (LON:AZN) and Shire Plc (LON:SHP) made large gains on Thursday following the release of the Senate Republicans’ healthcare plan.

The bill aims to repeal and replace Obamacare, with deep cuts to Medicaid funding and the re-shaping of subsidies to low-income people for private insurance.

Analysts suggested that the new bill – which is set to be put to a vote before the 4 July break – could be more beneficial to big pharma than originally expected.

Healthcare stocks were also one of the best performers earlier this week on high hopes for eased regulations in the industry.

The Trump administration is reportedly drafting an executive order that would ease regulatory burdens on drugmakers in order to try and drive down drug prices.

Like their UK counterparts, US pharma companies have also zipped higher this week. The S&P healthcare index rose another 1% yesterday, hitting a record close for the fifth day in a row.

Analysts have also suggested that the uptick in the sector could also be down to investors moving away from technology stocks and looking to invest elsewhere.

AstraZeneca gained 2% on Thursday to £55.08, GSK finished 2.3% higher at £17.22, while Shire added 3.7% to £46.26.


Antidepressant could help fight dementia

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Researchers discover antidepressant drug trazodone hydrochloride could help those with Alzheimer’s disease by reducing brain shrinkage, preventing cell death and improving memory.

Some 850,000 people currently suffer from dementia in the UK. And with this figure set to reach one million by 2025, the scale of the problem facing health services is obvious. Now, a study published in the journal Brain by researchers at Cambridge University, have found that trazodone hydrochloride, a drug already prescribed as an antidepressant, may be able to prevent the brain shrinkage and cell death caused by neurodegenerative diseases such as Alzheimer’s disease.

So far the drug has only been tested in mice, but as it has already been approved for human use it could be fast-tracked into clinical trials. “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias,” explained research lead Prof Giovanna Mallucci. “We could know in two to three years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.”

In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, faulty proteins build up in the brain. As these proteins accumulate, a natural defence mechanism ‘switches off’ the vital production of new proteins. The team previously found a drug that was capable of switching this process back on and halting neurodegeneration, but the drug was toxic to humans.

To search for safe alternatives, they tested 1,040 different compounds, first in C. elegans, a worm often used in early drug-screening, and then in mice. In the mice, trazodone hydrochloride consistently prevented the emergence of signs of brain cell damage and reduced brain shrinkage.

“Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group,” said Mallucci. “We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”

They also found dibenzoylmethane, a compound undergoing trials as an anti-cancer drug, to be effective, though more work is required to determine its safety.


Phase 2 clinical study examines Alzheimer’s disease drug to treat adults with Down syndrome

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A phase 2 clinical trial in young adults with Down syndrome of a drug being investigated for the treatment of Alzheimer’s disease supports further investigation of its potential.

Results of the four-week trial of scyllo-inositol, also known as ELND005, have been published in the Journal of Alzheimer’s Disease.

“Through this study, members of the Down syndrome community have demonstrated loudly and clearly that they are eager to participate in clinical trials, particularly studies that provide promise for the treatment of Alzheimer’s disease,” says Brian Skotko, MD, MPP, co-director of the Massachusetts General Hospital (MGH) Down Syndrome Program, and a site principal investigator for the trial. “This first, industry-sponsored phase 2 trial in the Down syndrome community showed that people with Down syndrome were able to follow the study protocol and that the drug was safe and tolerable.”

The most common form of intellectual disability in the United States, Down syndrome is caused by an extra copy of chromosome 21. People with Down syndrome exhibit various degrees of intellectual disability and are at greatly increased risk of developing Alzheimer’s dementia as they age. Excess activity of the genes on chromosome 21 – including the gene for the amyloid precursor protein, the source of amyloid plaques found in the brains of people with Alzheimer’s disease – is thought to play a role in the cognitive challenges of people with Down syndrome.

Another chromosome 21 gene believed to play a role in Down syndrome contributes to the metabolism of myo-inositol, a signaling molecule increased in the brains of children and adults with Down syndrome at levels that correlate to the severity of symptoms. Lifelong exposure to increased levels of both amyloid and myo-inositol are believed to contribute to brain dysfunction and cognitive disability. Scyllo-inositol may have potential to improve cognition in patients with Down syndrome both by decreasing amyloid levels and regulating myo-inositol-dependent signaling in the brain.

The clinical trial enrolled 23 adults with Down syndrome, ages 18 to 45, who were randomized to receive one of two dosages of scyllo-inositol – 250 mg either daily or twice a day – or a placebo. All but one participant completed the four-week trial with no significant deviations from the protocol. There were no serious adverse events and no changes in vital signs, laboratory tests or other physical findings. While treatment produced no apparent cognitive or behavioral changes, the duration of the trial was too short to capture such effects.

“Scyllo-inositol has been extensively tested in the typical Alzheimer’s disease population, but this study looked at it specifically in people with Down syndrome who are at an increased risk for AD,” says Michael Rafii, MD, PhD, clinical director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California and associate professor in the Department of Neuroscience at the University of California, San Diego, lead and corresponding author of the study. “The results of this study are encouraging, and further study of this compound in Down syndrome should certainly be considered.”


MSD makes €280m pledge

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Biopharmaceutical giant MSD is creating more than 300 jobs at its Carlow and Cork manufacturing sites as part of a €280m (£245m) investment.

The proposed cash injection is as a result of increased global demand for MSD’s medicines and vaccines produced in Ireland, with both sites to expand production facilities and capacity.

The majority of the 330 roles will be based in Cork, with about 120 in Carlow. Available positions will include technical, engineering, biochemistry, biology, quality and operations.

Minister Mary Mitchell O’Connor said she “warmly welcomed” the new investment and additional jobs.

“MSD has been at the cutting edge of biopharmaceutical innovation over recent years and their Irish operations are at the heart of many of the company’s exciting new products,” she added.

Sanat Chattopadhyay, MSD executive vice president and president of the company’s manufacturing division, added: “Today’s announcement is a reflection of MSD Ireland’s positive standing in our global network, a vote of confidence in our people and their work, and a sign of MSD’s future commitment to Ireland.

“The expansion of our presence in Ireland is a testament to the talent of our Irish employees. In recent years our Irish businesses have played an increasingly important role in the production of some of MSD’s most important breakthrough medicines for the global market.”

MSD currently employs more than 1,600 staff across four sites in Ireland – Carlow, Cork, Dublin and Tipperary.


Silence Therapeutics appoints former Roche luminary Torsten Hoffman as chief operating officer

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Silence Therapeutics appoints former Roche luminary Torsten Hoffman as chief operating officer.

“I have been impressed with his energy and the way that he has quickly formed a close working relationship with our chief scientific officer, Dmitry Samarsky,” said Ali Mortazavi, CEO of Silence.

Silence Therapeutics PLC (LON:SLN) has appointed Torsten Hoffman, formerly chief scientific officer of biotech Proteros Biostructures, as its chief operating officer.

Hoffmann will report directly to chief executive officer Ali Mortazavi.

Hoffmann spent 16 years at drugs giant Roche, and was the lead inventor of netupitant, discovered at Roche and approved by the US Food and Drug Administration as Akynzeo in 2014.

“As we continue to make progress with our new GalNAc-based platform, Torsten brings an experienced rigour to our operations with his knowledge from target selection through to clinical trials,” Mortazavi said.

“As a consultant, he has already enabled us to drive efficiency through outsourcing certain activities and he will add further immediate benefits in the field of gene target selection and novel RNA therapeutics, helping to further differentiate Silence in delivering high quality medicines for better patients’ lives,” he added.

Shares in Silence were off a penny at 97.25p in the first hour of trading.


Atlantic develops tablet formulations of alicaforsen to treat Crohn’s disease

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Atlantic Healthcare announces the development of two separate tablet formulations of alicaforsen, for targeted delivery in the GI tract…

Atlantic Healthcare, an emerging trans-Atlantic pharmaceutical company with a core focus on gastrointestinal (GI) disorders, announces the development of two separate tablet formulations of alicaforsen, for targeted delivery in the GI tract, to treat Crohn’s disease and Ulcerative Colitis (UC).

Atlantic Healthcare is preparing Phase 1 trials that are designed to confirm safety and the release profile of the drug at the appropriate site in the GI tract. The UC formulation is designed to release at the terminal ileum for delivery to the colon, and the formulation for Crohn’s disease is designed to release in the small intestine.

Enema formulation

Alicaforsen, as an enema formulation, is currently being evaluated in a pivotal Phase 3 trial, and has initiated its rolling submission to the US Food and Drug Administration (FDA), to treat pouchitis, a rare and serious form of inflammatory bowel disease (IBD) that has limited treatment options. The company plans to commercialise alicaforsen in the US and Europe and licence commercial rights in the rest of the world.

Toby Wilson Waterworth, CEO at Atlantic Healthcare said, “The development and approval of alicaforsen tablet formulations would complement the existing enema, and substantially expand the commercial potential of the product. The two new tablet formulations are designed to deliver alicaforsen to specific points in the GI tract, inaccessible to the enema, to treat Crohn’s disease and UC.

Additional options

Alicaforsen has the potential to treat multiple GI inflammatory diseases. We are very excited by the prospect of providing clinicians and patients with additional options to treat these serious diseases, which have substantial unmet clinical need.”

Dr Janette Thomas, Director of International Operations at Atlantic Healthcare said: “The new tablet formulations harness recent advances in encapsulation and targeted-release technologies for oligonucleotides such as alicaforsen. The aim is to deliver the product to sites of disease, with minimal systemic absorption.

Based on the existing clinical and safety data that includes treatment in over 1,000 patients, a positive read-out from Phase 1, confirming safety and drug release at the appropriate site of disease in the GI tract, would enable progression to Phase 2b, dose escalation studies.”


NICE u-turn backs Sanofi’s Gaucher disease drug

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It is now looking likely that Sanofi’s Cerdelga will be funded on the NHS in England and Wales to treat type 1 Gaucher disease, after a u-turn by cost regulators.

The National Institute of Health and Care Excellence (NICE) has issued a positive Final Evaluation Determination (FED) recommending Cerdelga (eliglustat) as a first-line treatment for adults with the condition within its marketing authorisation, superseding a previous provisional rejection.

Gaucher disease is a very rare, inherited and potentially life-threatening genetic condition which is incurable but can be managed with effective treatment.

It is caused by a deficiency of an enzyme (glucocerebrosidase) which leads to the build-up of complex lipids (fatty substances) in some types of blood cells. These are known as Gaucher cells and occur throughout the liver, spleen, bone marrow and occasionally the lungs.

The current standard of care in the UK is enzyme replacement therapy, but long-term reliance on these intravenous infusions “are not suitable or practical for all,” says Sanofi, underscoring the need for new treatment options.

Unlike enzyme replacement therapy, Cerdelga is a substrate reduction therapy that partially inhibits an enzyme called glucosylceramide synthase, resulting in reduced production of glucosylceramide (the fatty substance which accumulates in people with Gaucher disease) and Gaucher cells.

EU approval of the twice-daily pill back in 2015 was based on data from the largest clinical research programme ever conducted in Gaucher disease type 1 at the time, involving around 400 patients, which showed that Cerdelga improved a variety of endpoints including spleen size, platelet levels, hemoglobin levels, and liver volume, and also showed non-inferiority to the enzyme replacement therapy Cerezyme (imiglucerase).

’The news that NHS England will fund an oral treatment for type 1 Gaucher disease in England will be welcomed within the Gaucher community,” comments Tanya Collin-Histed, chief executive of Gauchers Association, UK.

“With this decision patients in England, in consultation with their Gaucher Consultant, will be able to choose a treatment that best suits their needs. Having the option of either oral or IV therapy available on the NHS will give many patients access to a new therapeutic opportunity.”

Final guidance is expected later this month.