Saturday, May 12, 2018

What Does the Research Say About Coffee and Your Health?


In continuation of my update on coffee...

Image result for coffee


Coffee-Cup of joe. Java. No matter what you call it, millions of people worldwide wake up and fuel their day with it. And though consumers might be jittery about the recent court battle in California over cancer warnings, experts say most of the science actually indicates coffee could have health benefits.

"The overall picture is quite clear," said Dr. Frank Hu, chair of nutrition at Harvard University's T.H. Chan School of Public Health. "There is no long-term increased risk of major chronic disease, including diabetes, cardiovascular disease or even cancer."
The java confusion stems over an eight-year court case. A Los Angeles-based judge's preliminary decision last month requires cancer warning labels because of concerns about acrylamide, a chemical produced during the roasting process. Acrylamide also is present in some fried or roasted starchy foods, including french fries, potato chips, breakfast cereals and toast. It's also found in cigarette smoke. The judge gave the coffee industry a few weeks to file appeals and could issue a final ruling late this month.
But there's little evidence acrylamide levels in food cause cancer in humans. Studies have found no consistent evidence acrylamide exposure in food is associated with cancer risk, according to the U.S. National Cancer Institute. The World Health Organization's International Agency for Research on Cancer reviewed more than 1,000 human and animal studies and issued a statement in 2016 that "found no conclusive evidence for a carcinogenic effect of drinking coffee."
"The California judge's decision to label coffee as a cancer risk is really inconsistent with the scientific literature," Hu said. "It's very misleading and has already caused a huge amount of confusion in the general public. The health outcomes have been remarkably consistent."
Hu was senior author of a 2015 study in the journal Circulation that concluded people who regularly drink moderate amounts of coffee daily -- fewer than five cups -- experienced a lower risk of death from heart and neurological diseases.
About four years ago, the U.S. government gave coffee its OK, too. The Department of Agriculture's dietary guidelines for all Americans, published every five years as a go-to source for nutrition advice, said three to five cups a day, which can be up to 400 milligrams a day of caffeine, can be part of a healthy diet. The American Heart Association suggests that people who have an arrhythmia, an abnormal heart rhythm, talk to their health care provider about caffeine intake.
"This guidance on coffee is informed by strong and consistent evidence showing that, in healthy adults, moderate coffee consumption is not associated with an increased risk of major chronic diseases (e.g., cancer) or premature death, especially from cardiovascular disease," the federal guidelines say. "However, individuals who do not consume caffeinated coffee or other caffeinated beverages are not encouraged to incorporate them into their eating pattern."
More recently, a review of more than 200 studies published last fall in the BMJ concluded three to four cups a day may be "more likely to benefit health than harm." It found a lower risk of liver disease and some cancers in coffee drinkers, and a lower risk of dying from stroke.
All of that should be good news to the people around the world who drink more than 1.1 billion cups of coffee each day.
But it's still easy to be confused. A quick search for coffee and health online yields hundreds, even thousands, of results.
Studies abound -- some funded by the coffee industry. For example, a European Journal of Nutritionstudy investigated the effects of coffee and its antioxidant properties and found no effect. Researchers took blood samples of 160 volunteers who drank up to three to five cups of coffee or water each day for eight weeks.
"Up to five cups of coffee per day had no detectable effect, either beneficial or harmful, on human health," that study concluded. It was funded by Kraft Foods, which makes Maxwell House coffees.
Of course, "no one is talking about coffee as a magic bullet," Hu said. He and other experts say it's important to keep track of the bigger picture, with the focus on moderation and dietary patterns.
"You can't pin anything on any one specific lifestyle behavior, particularly with diet," said Alice Lichtenstein, a senior scientist and director of the Cardiovascular Nutrition Laboratory at Tufts University in Boston.
"When we talk about diet, it should really be about the whole package, not single items. Right now, the majority of the evidence suggests there may be a health benefit from drinking coffee and there doesn't seem to be any disadvantage. Of course, with a caveat that you don't want to add a lot of cream and sugar, or to use it as an excuse to have a few cookies or a pastry. Then, there is a downside," said Lichtenstein, a professor of nutrition science and policy who also was an advisor on the federal dietary guidelines.
"We have a tendency to focus on one or two specific foods or beverages, and that's when the whole floor falls out from under us."

Friday, May 11, 2018

FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia

Rigel Pharmaceuticals, Inc.   announced that the U.S. Food and Drug Administration (FDA) approved Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the disease by impeding platelet destruction, providing an important new treatment option for adult patients with chronic ITP. Rigel plans to launch Tavalisse in the United States in late May 2018.

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"Chronic ITP is challenging to treat because the heterogeneity of the disease makes it difficult to predict how an individual patient will respond to available treatments and not all patients can find a treatment that works well for them," said James Bussel, M.D., professor emeritus of pediatrics at Weill Cornell Medicine and the principal study investigator on the FIT Phase 3 program. Dr. Bussel has served as a consultant and paid member of the advisory board for Rigel Pharmaceuticals, Inc. "The FDA approval of fostamatinib arms physicians with a new treatment option, which works via a novel mechanism."
The FDA approval of Tavalisse was supported by data from the FIT clinical program, which included two randomized placebo-controlled Phase 3 trials (Studies 047 and 048) and an open-label extension (Study 049), as well as an initial proof of concept study. The New Drug Application (NDA) included data from 163 ITP patients and was supported by a safety database of more than 4,600 subjects across other indications in which fostamatinib has been evaluated.
"People living with chronic ITP often feel they have an invisible disease -- one that can not only impact quality of life, but also be life threatening," said Caroline Kruse, executive director of the Platelet Disorder Support Association, a patient advocacy organization dedicated to ITP patients. "That's why we encourage members of our community to learn about their disease, understand treatment strategies, and seek support so that they can advocate for their best care. The availability of a new treatment option provides the ITP community with more choices."


Thursday, May 10, 2018

Scientists successfully test anti-alcoholism drug in animal models

Scientists at The University of Texas at Austin have successfully tested in animals a drug that, they say, may one day help block the withdrawal symptoms and cravings that incessantly coax people with alcoholism to drink. If eventually brought to market, it could help the more than 15 million Americans, and many more around the world who suffer from alcoholism stay sober.
If what has been shown to work in worms and rats addicted to alcohol can eventually be demonstrated to work in humans with minimal side effects, it would be a true breakthrough. Scientists point out, however, that the drug has more hoops to go through before that happens.
There are already drugs on the market prescribed to help people break their addiction to alcohol, but for many patients, they are not very effective and have negative side effects. The new drug, called JVW-1034, targets a different molecular pathway in the body and so far, in animal models, has no obvious side effects.
"There's clearly a huge need for something different and better," said James Sahn, research scientist in chemistry at UT Austin and co-first author of a new paper. "That's where our approach shines. It's modulating a pathway that doesn't seem to be associated with any of the other drugs that are available."
The researchers reported their findings in the journal Neuropsychopharmacology and have filed a patent on the drug.
The paper's other co-first authors are Luisa Scott, a research associate in neuroscience at UT Austin; and Antonio Ferragud, a postdoctoral associate at Boston University School of Medicine (BUSM). Senior authors are Stephen Martin, professor of chemistry, and Jonathan Pierce, associate professor of neuroscience, both at UT Austin; and Valentina Sabino, associate professor of pharmacology and psychiatry at BUSM.
While the drug is promising, the researchers plan to optimize its chemical properties to have a better chance of being effective in humans. They envision a pill that could one day be taken to block alcohol withdrawal symptoms and cravings, helping people avoid relapsing. But it isn't clear whether such a drug could actually cure alcoholism. That's because there are genetic and regulatory underpinnings to the disorder that researchers don't fully understand yet and that may not be permanently altered by this drug. But even a drug that could be taken chronically or in times of stress could have a huge benefit for people suffering from alcoholism.
"If we could achieve a medication that is effective for more people and doesn't have the negative side effects that some of these drugs have, that would be game-changing," said Martin.
It might also make a dent in the $250 billion annual cost of alcohol misuse in the U.S., as estimated by a 2015 study.
This work was supported by The Robert A. Welch Foundation, the Dell Medical School's Texas Health Catalyst program, donations from individuals including Tom Calhoon and June Waggoner through a crowdfunding program called Hornraiser, and the National Institute on Alcohol Abuse and Alcoholism.
Screening in Worm and Rat Models
The drug JVW-1034 was named in honor of James Virgil Waggoner, a UT Austin alumnus, businessman and philanthropist who donated funds to establish the university's Waggoner Center for Alcohol and Addiction Research.
It was one of many potential compounds developed in the lab by chemists Stephen Martin and James Sahn, which they suspected would interact with a cell receptor found throughout the central nervous systems of animals, called sigma 2. Other researchers had shown that that receptor was involved in cocaine addiction. So Martin and Sahn wondered whether it might also be involved in alcoholism.
To screen their compounds, their colleague Luisa Scott created hungover worms. She exposed C. elegans worms to alcohol for a day and then took it away. She could tell they were hungover because when she placed a tasty-smelling substance on the other side of their petri dish, they sluggishly meandered over.
"It smells like movie theater popcorn," Scott said. "Normal worms are quite speedy, but withdrawal worms go very slowly."
When she administered JVW-1034 to the hungover worms, they once again raced across the dish just like worms that had never been exposed to alcohol.
In follow-up experiments, Scott demonstrated that the receptor sigma 2 was in fact the target of JVW-1034. This also demonstrated for the first time that sigma 2 is involved in alcohol addiction. She noted that it can be difficult to identify which parts of an animal's cells a drug interacts with. In fact, scientists still don't know the targets of many drugs that have been in use for many years.
"So for me, being able to show that this really is the target it binds to, that's a big deal," she said.
Finally, a group of collaborators led by Valentina Sabino tested JVW-1034 in alcoholic rats. Alcoholic rats that could freely access alcohol and were then given JVW-1034 dramatically reduced their alcohol consumption.
The researchers are developing several other promising drugs that target the sigma 2 receptor to treat other neurological disorders, including traumatic brain injury, neuropathic pain and Alzheimer's disease.

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

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In continuation of my update on OsimertinibAstraZeneca,announced that the US Food and Drug Administration (FDA) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test. The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: “Today’s FDA approval of Tagrisso in the 1st-line setting is an exciting milestone for patients and our company. Tagrisso delivered unprecedented median progression-free survival data across all pre-specified patient subgroups, including patients with or without CNS metastases, and could prolong the lives of more patients without their tumors growing or spreading.”
Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from Winship Cancer Institute of Emory University, Atlanta, said: “The approval of osimertinib (Tagrisso) in the 1st-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib (Tagrisso) provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors.”
The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC. Tagrisso met the primary endpoint of progression-free survival (PFS) (see table below). PFS results with Tagrisso were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.
*Confirmed responses
Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions (≥20%) in patients treated with Tagrisso were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%) and decreased appetite (20%).
In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test. In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.
Tagrisso received its first approval for 1st-line use based on the FLAURA data in Brazil in patients with metastatic EGFRm NSCLC on April 16, 2018.


Tuesday, May 8, 2018

FDA Approves Intravenous Formulation of Akynzeo (fosnetupitant/palonosetron) for Chemotherapy-Induced Nausea and Vomiting

Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, today announces that the U.S. Food and Drug Administration (FDA) has approved the intravenous formulation of Akynzeo (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing CINV.

Skeletal formula of fosaprepitant     Palonosetron structure.svg

The FDA has approved Akynzeo IV (formulation of fosnetupitant first structure  and palonosetron second structure) in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Akynzeo for injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.
Oral Akynzeo was previously approved by the FDA as a fixed combination oral agent in 2014 for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Akynzeo is an oral fixed combination of palonosetron and netupitant: palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.
The bioequivalence of the IV with the oral formulation of netupitant was demonstrated and the safety of IV NEPA was established through a repeated dose safety study in cancer patients to potentially uncover adverse drug reactions that may appear during subsequent clinical practice. No anaphylactic and injection site reactions related to IV NEPA were reported in this study.
Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting.
The prevention of CINV has been refined in treatment guidelines over the past several decades. Currently the combination treatment of antiemetic medicines with different mechanisms of actions are recommended for the prevention of CINV.
The approval of Akynzeo in IV formulation will offer to US patients and healthcare providers an alternative route of administration of the only fixed antiemetic combination targeting two distinct CINV pathways in a single dose.
Riccardo Braglia, Helsinn Group Vice Chairman and CEO, commented: “The approval of the intravenous formulation of Akynzeo paves the way to bring this important therapeutic option to more patients in a new formulation, and we are delighted that we are now able to push ahead with launching this product in the United States in May 2018”

Tuesday, April 24, 2018

FDA Approves Erleada (apalutamide) for Non-Metastatic Castration-Resistant Prostate Cancer

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The U.S. Food and Drug Administration, has approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.

“The FDA evaluates a variety of methods that measure a drug’s effect, called endpoints, in the approval of oncology drugs. This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public."
According to the National Cancer Institute (NCI) at the National Institutes of Health, prostate cancer is the second most common form of cancer in men in the U.S.. The NCI estimates approximately 161,360 men were diagnosed with prostate cancer in 2017, and 26,730 were expected to die of the disease. Approximately 10 to 20 percent of prostate cancer cases are castration-resistant, and up to 16 percent of these patients show no evidence that the cancer has spread at the time of the castration-resistant diagnosis.
Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.
The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or with surgery to lower the amount of testosterone in their body (surgical castration). The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.
Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).
Severe side effects of Erleada include falls, fractures and seizures.
This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
The sponsor for Erleada is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, certain information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.

Monday, April 23, 2018

FDA Approves Symdeko (tezacaftor/ivacaftor and ivacaftor) to Treat Cystic Fibrosis in People Ages 12 and Older with Certain Mutations in the CFTR Gene

Vertex Pharmaceuticals Incorporated announced  the U.S. Food and Drug Administration (FDA) approval of  Symdeko (tezacaftor/ivacaftor and ivacaftor) for treating the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or who have at least one mutation that is responsive to tezacaftor/ivacaftor. Symdeko is Vertex's third medicine approved to treat the underlying cause of CF. Vertex is ready to launch Symdeko and will begin shipping it to pharmacies in the United States this week.

Ivacaftor.svgIvacaftoTezacaftor.pngtezacaftor
"Today is an exciting day for the CF community. The approval of Symdeko, our third disease-modifying CF medicine, offers many patients an important new treatment option," said Jeffrey Leiden, M.D., Ph.D., Vertex's Chairman, President and Chief Executive Officer. "This approval is an important milestone in our journey to treat every person with CF, and we remain committed to urgently advancing our efforts to develop new medicines that treat the underlying cause of CF for the many people still waiting."
In November 2017, the New England Journal of Medicine published the results of two Phase 3 studies of Symdeko. These studies, named EVOLVE and EXPAND, enrolled approximately 750 people with CF ages 12 and older with two copies of the F508del mutation or with one F508del mutation and one mutation that results in residual CFTR function. Across both studies, patients treated with Symdeko experienced statistically significant and clinically meaningful improvements in lung function and other measures of disease, with a favorable safety profile. The most common adverse events, regardless of treatment group, included infective pulmonary exacerbation and cough. The first data from the ongoing EXTEND rollover study, also presented in November, show that the lung function improvements and the safety and tolerability profiles seen in EVOLVE and EXPAND were sustained for up to 48 total weeks of Symdeko treatment.
"We've already seen the significant impact that disease-modifying medicines can have on patients and are incredibly pleased that there is now a third treatment option that enables more patients to benefit from CFTR modulation," said Patrick Flume, M.D., Director of the Medical University of South Carolina Cystic Fibrosis Center and Principal Investigator for the EXTEND study. "In particular, Symdeko is an important treatment option for patients who either never started or discontinued Orkambi, and it also provides increased benefit over Kalydeco alone for patients with residual function mutations."
The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for the tezacaftor/ivacaftor combination. The company expects approval in the EU in the second half of 2018.

Friday, April 20, 2018

CutisPharma Announces FDA Approval of Firvanq (vancomycin) for Treatment of Clostridium Difficile Associated Diarrhea and Staphylococcus Aureus Colitis


In continuation of my update on vancomycin

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CutisPharma announced  the US Food and Drug Administration (FDA)  approval of  Firvanq (vancomycin hydrochloride) for oral solution, for the treatment of Clostridium difficile associated diarrhea and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains.

“We are pleased to announce the FDA approval of Firvanq,” said Neal I. Muni, MD, MSPH, Chief Executive Officer of CutisPharma. “Firvanq's approval is an important step forward to providing patients the only FDA-approved vancomycin oral liquid treatment option for Clostridium difficile associated diarrhea, a life-threatening condition that affects over a half-million patients in the United States annually.”
Upon its launch, which is targeted to be April 2, 2018, Firvanq will replace CutisPharma’s FIRST®-Vancomycin Unit-of-Use Compounding Kit, which has been available to pharmacists that need a convenient, accurate, and compliant way to compound vancomycin oral liquid therapy. Firvanq will be commercially available in 25 mg/mL and 50 mg/mL strengths in convenient 150 mL and 300 mL sizes. Firvanq is designed to be easy to use and has the potential to be a cost-effective alternative to existing vancomycin therapies.
“As a practicing infectious disease physician treating many patients with CDAD, having an FDA-approved vancomycin oral liquid formulation that is affordable and accessible to my patients is very beneficial,” said Stuart Johnson, MD, Loyola University Medical Center. “Patient access is currently limited by the fact that only a select few pharmacies perform compounding in the outpatient setting these days, given the many new regulations in place. Availability of an FDA-approved vancomycin oral liquid treatment will effectively allow any pharmacy to stock this therapy, and hopefully encourage third-party payer reimbursement, significantly improving accessibility and convenience for patients.”

Thursday, April 19, 2018

FDA Approves Osmolex ER (amantadine) for the treatment of Parkinson’s Disease and Drug-Induced Extrapyramidal Reactions



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In continuation of my update on amantadine

Osmotica Pharmaceutical US LLC, announced the  U.S. Food and Drug Administration (FDA) has approval Osmolex ER, an amantadine extended release tablet, for the treatment of Parkinson's disease and for the treatment of drug-induced extrapyramidal reactions in adult patients. Extrapyramidal symptoms are known side effects of many common medications.

“The FDA’s approval of Osmolex ER provides a new treatment option for those patients suffering from Parkinson’s disease and adults who have extrapyramidal reactions, or movement disorders, that are caused by certain medicines. We are eager to make Osmolex ER available to physicians and patients in the U.S.,” stated Brian Markison, Chief Executive Officer of Osmotica.
“We are currently finalizing our plans to commercialize the product and ensure patients and providers have access as soon as possible. We believe that the approved indications and compelling value proposition will be important factors in physician adoption and marketing of Osmolex ER,” added Markison.
Osmolex ER tablets, a proprietary drug formulation containing a combination of immediate release and extended release amantadine utilizing Osmotica’s patented Osmodex® technology, represents a new once-a-day approach to the treatment of Parkinson’s disease and drug-induced involuntary movements in adults. The Osmolex ER tablet is taken once-daily in the morning, releasing amantadine throughout the day. Physicians have three dosage options with 129 mg, 193 mg and 258 mg tablets, with a maximum daily dose of 322 mg, providing them with dosing flexibility for each patient.
Osmolex ER is protected by three formulation patents with protection extending through March 2030, with additional patent applications pending.

Wednesday, April 18, 2018

New class of antimicrobial polymers can kill five hard-to-treat multidrug-resistant bacteria



An international research team led by the Institute of Bioengineering and Nanotechnology (IBN) of the Agency for Science, Technology and Research (A*STAR) and IBM Research developed a synthetic molecule that can kill five deadly types of multidrug-resistant bacteria with limited, if any, side effects. Their new material could be developed into an antimicrobial drug to treat patients with antibiotic-resistant infections. This finding was reported in the scientific journal Nature Communications.


Superbugs that are resistant to antibiotics are a serious health threat. According to the UK Review on Antimicrobial Resistance, superbugs kill around 700,000 people worldwide each year. By 2050, 10 million people could die each year if existing antibiotics continue to lose their effectiveness.
“There is an urgent global need for new antimicrobials that are effective against superbugs. The situation has become more acute because bacteria are starting to develop resistance to the last-line antibiotics, which are given only to patients infected with bacteria resistant to available antibiotics,” said Professor Jackie Y. Ying, Executive Director of IBN.
The research community is trying to develop alternatives to antibiotics using synthetic polymers. However, the antimicrobial polymers developed so far are either too toxic for clinical use, not biodegradable or can only target one type of bacteria.
To address this problem, Dr Yi Yan Yang from IBN brought together a multidisciplinary research team from the US, China and Singapore to develop a new class of antimicrobial polymers called guanidinium-functionalized polycarbonates with a unique killing mechanism that can target a broad range of multidrug-resistant bacteria. It is biodegradable and non-toxic to human cells.
The polymer kills bacteria in the following way. First, the polymer binds specifically to the bacterial cell. Then, the polymer is transported across the bacterial cell membrane into the cytoplasm, where it causes precipitation of the cell contents (proteins and genes), resulting in cell death.
The team tested the polymers on mice infected with five hard-to-treat multidrug-resistant bacteria: Acinetobacter baumanniiEscherichia coliKlebsiella pneumoniaemethicillin-resistant Staphylococcus aureu and Pseudomonas aeruginosa. These superbugs are commonly acquired by patients in the hospitals and can cause systemic infections that lead to septic shock and multiple organ failure. The results showed that the bacteria were effectively removed from the mice and no toxicity was observed.
The researchers then further tested the effectiveness of the polymers on mice with two types of systemic infections caused by superbugs: peritonitis (an infection of the stomach’s inner lining) and lung infections from Pseudomonas aeruginosa. The polymers eliminated the bacterial infections in both groups of mice with negligible toxicity.
Dr Yi Yan Yang, Group Leader at IBN said:
We have demonstrated the first example of a biodegradable synthetic macromolecule with broad-spectrum antimicrobial activity in mice, unique killing mechanism and no toxicity. Once the polymer finishes its job of killing the bacteria, it will be naturally degraded after three days and will not remain in the body. This antimicrobial agent shows great promise for the treatment and prevention of multidrug-resistant systemic infections.
“This study illustrates the potential for this new research field we denote as ‘macromolecular therapeutics’ to create entirely new classes of treatments for multiple diseases,” said Dr James Hedrick, Distinguished Research Staff Member, IBM Research – Almaden, San Jose, California. “In 2016, we demonstrated the efficacy of synthetic polymers to combat deadly viral diseases. The current research for treating bacterial infections rounds out our ability to someday treat a spectrum of infectious diseases with a single, new type of mechanism without the onset of resistance.”
To determine whether the bacteria will develop any resistance to the polymer, the team collaborated with Dr Paola Florez de Sessions at A*STAR’s Genome Institute of Singapore and the Cell Engineering group of Dr Simone Bianco at IBM Research – Almaden to perform genomic analysis. They found that the bacteria did not show any resistance development even after multiple treatments with the polymer.
Ref :http://www.ibn.a-star.edu.sg/pdf/media_release/press_133.pdf
https://www.nature.com/articles/s41467-018-03325-6/figures/1