TSRI scientists develop first drug candidate that neutralizes disease-causing RNA repeats

Top, Venn diagram of substructures in compounds that were found to bind to RNA from the fluorescence screening assay showed in Fig. 1c. Data were compiled by using compounds that had a P value of <0.001 for binding to the RNA hairpins. Bottom, structures of compounds 1 and 2 that were the most avid for binding to AUAU and AAUU RNA hairpins.

In an important new study with implications for the treatment of dozens of incurable diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time created a drug candidate that attacks and neutralizes the RNA structure that causes an incurable progressive, inherited disease involving a gradual loss of control over body movement.

The study, which was published June 1, 2016 in Nature Communications, showed the compound significantly improved several aspects of cells taken directly from patients with spinocerebellar ataxia type 10 (SCA10), a form of spinocerebellar ataxia.

“More than 30 diseases, all of them incurable, are caused by RNA repeats,” said TSRI Professor Matthew Disney, who led the study. “By a thorough basic science investigation, we identified small molecules that target RNA base pairs precisely. We then leveraged this information to design the first drug candidate that binds to disease-causing defects in SCA10. Application of the drug candidate returns certain aspects of those cells to healthy levels—it’s like the defect is not even there.”

SCA10 is caused by what is called a pentanucleotide repeat (a genetic sequence of five nucleotides repeated many more times than normal) affecting the mitochondria, the cell’s energy source. The new drug candidate, known as 2AU-2, targets these repeats by binding to RNA base pairs.

“The potent bioactivity of 2AU-2 to moderate the structurally induced toxicity in SCA10 strongly suggests that base-pair-targeting RNA modules could have broad applicability in our effort to develop other compounds that target different RNAs,” said TSRI Research Associate Wang-Yong Yang, the first author of the study. “More than 70 percent of RNA secondary structure is made up of base pairing.”

The Disney group has developed new tools to identify optimal interactions between RNA structures and drug candidates targeting them. A database of these interactions has already been used to design several small molecule drug candidates.

“We are in the process of developing tools that allow one to design small molecules to target any RNA structural motif in a complex cellular environment. That environment can contain millions of other RNAs. In this study, Wang-Yong has done an exceptional job tackling this previously-thought-to-be-impossible molecular recognition problem,” Disney said.

Pathogenic RNA repeats contribute to disorders including Huntington’s disease, fragile X-associated tremor ataxia syndrome and myotonic dystrophy type 1 and 2.

Ref : http://www.nature.com/ncomms/2016/160601/ncomms11647/full/ncomms11647.html

Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties: Diflunisal -- a cousin of aspirin -- blocks a key protein that causes tumor formation in leukemia

In a study published in eLife, the researchers found that both salicylic acid and diflunisal suppress two key proteins that help control gene expression throughout the body. These sister proteins, p300 and CREB-binding protein (CBP), are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth. By inhibiting p300 and CBP, salicylic acid and diflunisal block the activation of these proteins and prevent cellular damage caused by inflammation. This study provides the first concrete demonstration that both p300 and CBP can be targeted by drugs and may have important clinical implications.

"Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we're still discovering new things about it," said senior author Eric Verdin, MD, associate director of the Gladstone Institute of Virology and Immunology. "Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs."

Earlier research conducted in the laboratory of co-author Stephen D. Nimer, MD, director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and a collaborator of Verdin's, established a link between p300 and the leukemia-promoting protein AML1-ETO. In the current study, scientists at Gladstone and Sylvester worked together to test whether suppressing p300 with diflunisal would suppress leukemia growth in mice. As predicted, diflunisal stopped cancer progression and shrunk the tumors in the mouse model of leukemia.

"The ability to repurpose drugs that are already FDA-approved to be part of novel therapies for cancer patients is incredibly exciting," said Nimer. "We have conducted a clinical trial of salicylic acid in patients with hematologic cancers and found it to be safe. Thus, this collaborative effort to develop novel epigenetic therapies is an important next step in our journey to find more effective treatment for leukemia patients."

The scientists are now pursuing a clinical trial that will test the ability of salicylic acid to treat patients with leukemia as part of novel combination therapies. Other possible clinical applications for salicylic acid include other forms of cancer, type 2 diabetes, inflammatory diseases, and even neurodegenerative disorders, such as Alzheimer's disease. Prior Gladstone research showed that another drug containing salicylic acid prevented the accumulation of tau in neurons and protected against cognitive decline in a mouse model of dementia.

First buprenorphine implant for opioid dependence treatment gets FDA approval

The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.

Until today, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person's cheek until it dissolved. While effective, a pill or film may be lost, forgotten or stolen. However, as an implant, Probuphine provides a new treatment option for people in recovery who may value the unique benefits of a six-month implant compared to other forms of buprenorphine, such as the possibility of improved patient convenience from not needing to take medication on a daily basis. An independent FDA advisory committee supported the approval of Probuphine in a meeting held earlier this year.

"Opioid abuse and addiction have taken a devastating toll on American families. We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives," said FDA Commissioner Robert M. Califf, M.D. "Today's approval provides the first-ever implantable option to support patients' efforts to maintain treatment as part of their overall recovery program."

Expanding the use and availability of medication-assisted treatment (MAT) options like buprenorphine is an important component of the FDA's opioid action plan and one of three top priorities for the U.S. Department of Health and Human Services' Opioid Initiative aimed at reducing prescription opioid and heroin related overdose, death and dependence.

Opioid dependence is the diagnostic term used for the more common concept, "addiction," in the Probuphine clinical trials. Addiction is defined as a cluster of behavioral, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence. Physical dependence is not the same as addiction. Newer diagnostic terminology uses the term "opioid use disorder," which includes both milder forms of problematic opioid use as well as addiction.

MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use, without causing the cycle of highs and lows associated with opioid misuse or abuse. At sufficient doses, it also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their opioid use disorder cut their risk of death from all causes in half.

"Scientific evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more effective in the treatment of opioid use disorder than short-term detoxification programs aimed at abstinence," said Nora Volkow, M.D., director of the National Institute on Drug Abuse at the National Institutes of Health. "This product will expand the treatment alternatives available to people suffering from an opioid use disorder."

Probuphine should be used as part of a complete treatment program that includes counseling and psychosocial support. Probuphine consists of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm and provide treatment for six months. Administering Probuphine requires specific training because it must be surgically inserted and removed. Only a health care provider who has completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants. If further treatment is needed, new implants may be inserted in the opposite arm for one additional course of treatment. The FDA is requiring postmarketing studies to establish the safety and feasibility of placing the Probuphine implants for additional courses of treatment.

The safety and efficacy of Probuphine were demonstrated in a randomized clinical trial of adults who met the clinical criteria for opioid dependence and were considered stable after prior buprenorphine treatment. A response to MAT was measured by urine screening and self-reporting of illicit opioid use during the six month treatment period. Sixty-three percent of Probuphine-treated patients had no evidence of illicit opioid use throughout the six months of treatment – similar to the 64 percent of those who responded to sublingual (under the tongue) buprenorphine alone.

The most common side effects from treatment with Probuphine include implant-site pain, itching, and redness, as well as headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain. The safety and efficacy of Probuphine have not been established in children or adolescents less than 16 years of age. Clinical studies of Probuphine did not include participants over the age of 65.

Probuphine has a boxed warning that provides important safety information for health care professionals, including a warning that insertion and removal of Probuphine are associated with the risk of implant migration, protrusion, expulsion and nerve damage resulting from the procedure. Probuphine must be prescribed and dispensed according to the Probuphine REMS program because of the risks of surgical complications and because of the risks of accidental overdose, misuse and abuse if an implant comes out or protrudes from the skin. As part of this program, Probuphine can only be prescribed and dispensed by health care providers who are certified with the REMS program and have completed live training, among other requirements.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

First buprenorphine implant for opioid dependence treatment gets FDA approval: The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.

Study identifies potential new treatment for subset of gastric cancer patients

Testing cancers for 'addiction' to a gene that boosts cell growth can pick out patients who may respond to a targeted drug under development, a major new study reports.

By measuring the number of copies of just one gene from cancer DNA circulating in the bloodstream, scientists were able to identify the patients with stomach cancer who were most likely to respond to treatment.

Stomach cancers with many copies of the FGFR2 gene were found to be particularly susceptible to the experimental drug, an FGFR inhibitor, because the tumours had become reliant on, or 'addicted' to, the gene in order to grow.

The new test, described in the prestigious journal Cancer Discovery this week, could be used in future to direct treatment, by identifying a subset of patients who could benefit from an FGFR2 inhibitor.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust assessed the potency of the FGFR inhibitor AZD4547 in patients with stomach and breast cancer in a phase II clinical trial that screened 341 patients.

The study was funded by Cancer Research UK and AstraZeneca, with some additional funding from the charity Breast Cancer Now and the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR).

Initially using tumour biopsies, researchers found many copies of the FGFR2 gene in 9 per cent of cancers among the 135 stomach cancer patients on the trial. Cancer cells often undergo changes in their DNA that can result in multiple copies of genes that help cancers grow and spread.

Tumours with multiple copies of the gene FGFR2 responded well to the treatment, with three out of nine patients having a response to treatment, and in those patients the drug worked for an average of 6.6 months.

Some 18 per cent of breast cancers were found to have multiple copies of a sister gene, known as FGFR1, and not FGFR2 - but tumours with multiple FGFR1 genes did not have the same susceptibility to the drug.

Interrogating the reason for their observations, the researchers took samples back to the laboratory to pick apart the reasons why the drug worked well in FGFR2 tumours and not in other FGFR genes.

Through painstaking experiments, they found that FGFR2 hijacks molecular pathways that help cancer grow and spread, and some stomach tumours become addicted to high levels of the gene's protein product.

This phenomenon is known as cancer gene 'addiction', and is a weakness that can be exploited by modern targeted therapies.

Study co-leader Dr Nicholas Turner, Team Leader in Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our study has identified a potential new treatment for a subset of patients with gastric cancer, and has explained why some gastric cancers were responding to treatment while others did not. We were able to design a blood test to screen for patients who were most likely to benefit from an FGFR2 inhibitor, helping us to target drug therapy at those patients who were most likely to benefit.

"The research helps shed light on how tumours can become addicted to certain cancer genes, and shows how we can treat the disease effectively by taking advantage of these weak points in cancer's armoury."

Professor David Cunningham, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Honorary Professor of Cancer Medicine at The Institute of Cancer Research, London, who was Chief Investigator of the clinical trial associated with the study, said:

"This is a great example of a faster, smarter treatment being delivered to a relatively small but important group of patients with gastric cancer, made possible through the support of our NIHR Biomedical Research Centre."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"This is an important study, which shows how new targeted treatments can exploit cancer's genetic addictions, and acts as a proof of principle that cancer DNA detected in the bloodstream can be used to guide treatment.

"This is a perfect example of not just bench to bedside but back again - showing the value in taking clinical findings and scrutinising them back in the lab."

Dr Emma Smith, Cancer Research UK's science information manager, said:

"Developing ways to identify people who are most likely to benefit from drugs targeting particular genetic faults is vital to help ensure each patient gets the most effective treatment. The next steps will be larger clinical trials to see if testing for this genetic abnormality can spot people whose stomach cancer will respond well to this treatment."

Dr Carl Barrett, VP Translational Science, Oncology iMed, Innovative Medicines & Early Development, AstraZeneca, said:

"This collaboration illustrates the importance of carefully analysing patient tissue samples to develop an understanding of markers of sensitivity and resistance. This knowledge will help future development of FGFR inhibitors and the understanding of the genomic response to treatment. The development of a blood-based biomarker assay, which will detect circulating tumour DNA, will help identify patients whose tumour is addicted to FGFR2 gene amplification events. AstraZeneca already uses this approach for several targeted therapies across our oncology portfolio."

Vismodegib drug shows no addded benefit in advanced or symptomatic metastatic BCC patients

  

Vismodegib (trade name: Erivedge) has already been approved since 2013 for the treatment of patients with locally advanced basal cell carcinoma (BCC) or symptomatic metastatic BCC and has already undergone an early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) limited its decision in February 2014 to two years, which is why the drug manufacturer now submitted a new dossier.

In its second early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) came to the same conclusion as in the first one: The data presented on the drug showed no superiority in comparison with the appropriate comparator therapy. Hence an added benefit of vismodegib is still not proven.

No better data two years later

The appropriate comparator therapy was best supportive care (BSC), i.e. an individual combination of the best possible supportive treatments. According to the G-BA, this can also include surgery or radiotherapy for patients with symptomatic metastatic BCC, which is not the case in locally advanced BCC.

As already in the first dossier, the manufacturer presented no data from randomized or non-randomized comparative studies that would be suitable for the assessment of an added benefit of vismodegib for patients with symptomatic metastatic BCC or with locally advanced BCC. In the newly submitted data from four one-arm intervention studies, patients with symptomatic metastatic BCC cannot be differentiated from study participants with metastases, but without symptoms (metastatic BCC), for example. Furthermore, study results on the outcome "objective response rate" were not presented adequately for locally advanced BCC patients; there was no information on size, number and location of skin lesions, for example. Hence the manufacturer did not implement one of the conditions of the G-BA's Limitation.

Manufacturer's assumptions on BSC not justified

Moreover, a simplified search conducted by IQWiG showed that the study pool on locally advanced BCC in the dossier was incomplete. The manufacturer stated that it had found no studies on BSC, for example. Besides two further potentially relevant studies, IQWiG identified one study (Horn 2003), however.

This study runs counter to the manufacturer's assumptions that no studies on BSC in patients with locally advanced BCC existed and that it could be assumed that patients with locally advanced BCC do not respond to BSC:In the study, 75 per cent of the patients with locally advanced BCC responded completely after three months; after 24 months, these were still at least 50 per cent. Furthermore, the manufacturer claimed that nothing was known on the occurrence of adverse events in BSC. The study Horn 2003 actually addressed this outcome, however: No serious adverse events were reported.

Overall, there was no hint of an added benefit of vismodegib in comparison with the appropriate comparator therapy for any of the two research questions.

Vismodegib drug shows no addded benefit in advanced or symptomatic metastatic BCC patients: Vismodegib (trade name: Erivedge) has already been approved since 2013 for the treatment of patients with locally advanced basal cell carcinoma (BCC) or symptomatic metastatic BCC and has already undergone an early benefit assessment according to the Act on the Reform of the Market for Medicinal Products.

Researchers find Aspergillus as interesting target for discovery of novel drugs

The fungus Aspergillus fumigatus produces a group of previously unknown natural products. With reference to plant isoquinoline alkaloids, these substances have been named fumisoquins. Researchers from Jena (Germany) discovered the novel substances together with their American colleagues while studying the fungal genome. The family of isoquinoline alkaloids contains many pharmacologically active molecules. This study, which has just been published in Nature Chemical Biology, shows that fungi and plants developed biosynthetic pathways for these complex molecules independently of each other. These findings make Aspergillus an interesting target for the discovery of novel drugs and their biotechnological production.

A large number of drugs used today originate from nature. Most of these molecules, which can be found with or without synthetic modifications and exert their beneficial effect on human health, are derived from microorganisms or plants. Thus, it is of great interest to discover novel active compounds in nature and use them for the treatment of diseases.

One well-known group of plant metabolites are the isoquinoline alkaloids. Today more than 2,500 different types are known and they are mainly found in poppy and barberry plants. Famous examples include the painkiller morphine or the cough remedy codein.

Together with colleagues from the US, scientists in the labs of Dirk Hoffmeister and Axel Brakhage at the Friedrich Schiller University in Jena found out that fungi synthesize certain natural products in a very similar way to plants. They analyzed the genome of the common mold Aspergillus and discovered a small cluster of genes whose function was previously unknown. Comparing these genetic sequences with known data implied that they might be responsible for the synthesis of novel natural products.

By manipulating the genetic sequences, characterizing the resulting metabolites and using radioactive labeling experiments it was possible to elucidate the structure of the novel molecules and to unravel the detailed biosynthetic pathways. The researchers discovered a new linkage mechanism for carbon atoms which had never been seen before in fungi. The whole fumisoquin biosynthetic pathway appears to be a combination of plant biosynthetic principles and the non-ribosomal peptide synthetases commonly found in fungi.

Axel Brakhage, university professor and head of the Leibniz Institute for Natural Product Research and Infection Biology, explains: "Fungi and plants diverged early on during evolution. The newly discovered fumisoquin synthesis pathway shows that there was a parallel development for the production of isoquinoline alkaloid compounds in both groups of organisms. This opens up new roads for combinatorial biotechnology in order to advance the search for novel active compounds and thus to develop urgently needed new drugs."

Pre-treatment with antihistamines may suppress gastrointestinal symptoms of food allergy

Simultaneous pre-treatment with antihistamines that block both the H1 and H4 antihistamine receptors suppressed the gastrointestinal symptoms of food allergy in mice, according to researchers at National Jewish Health. The findings, published online in the journal Allergy, provide new insight into the development of food allergy and suggest potential therapies for prevention and treatment of food allergy.

Although recent findings have suggested that early exposure to peanuts can help prevent peanut allergy, the only effective therapy currently available for existing cases remains avoidance.

Histamine is a key participant in most allergic diseases including asthma, hay fever, and food allergy. When released by basophils or mast cells it can trigger a variety of symptoms, including inflammation, itchiness and mucus production. There are four histamine receptors found on a wide variety of cells in the body. Most commercially available antihistamines block only the H1 antihistamine receptor.

Meiquin Wang, MD, PhD, Erwin Gelfand, MD, and their colleagues at National Jewish Health pretreated mice sensitized to peanut with the H1 receptor antagonist loratadine (Claritin), and the experimental H4 receptor antagonist JNJ7777120, separately and in combination.

Separately, the two antihistamines had some effect on the intestinal response of the sensitized mice to peanut. When mice were pre-treated with both antihistamines together, diarrhea, intestinal inflammation and other symptoms were almost completely blocked. In vitro experiments indicated that the antihistamines work by suppressing the accumulation and function of dendritic cells, which take up peanut protein and present it to T cells of the immune system.

Aliskiren fails to show benefit for heart failure patients with diabetes

In continuation of my update on Aliskiren   and  Enalapril

 Enalapril  Aliskiren

A subgroup analysis in heart failure patients with diabetes from the ATMOSPHERE trial has failed to show benefit and signals the end of the road for aliskiren in heart failure. The findings were presented for the first time today in a late breaking trial session at Heart Failure 2016 and the 3rd World Congress on Acute Heart Failure.

"This was a subgroup analysis with the inherent limitations of this type of study. It failed to show superiority or non-inferiority of aliskiren over the angiotensin-converting enzyme (ACE) inhibitor enalapril in heart failure patients with diabetes," said principal investigator Professor Lars Kober, a consultant cardiologist at Rigshospitalet - Copenhagen University Hospital in Copenhagen, Denmark.

He continued: "The result may have been positive had the European Medicines Agency (EMA) not asked us to withdraw patients with diabetes from the trial. We will never know, as the angiotensin receptor neprilysin inhibitor LCZ696 has since emerged and bypassed the need for aliskiren."

Aliskiren is a renin-angiotensin-aldosterone system inhibitor that is used in patients with hypertension. The Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE) included 7016 patients with heart failure and reduced left ventricular ejection fraction, of whom 2340 were randomly assigned to enalapril plus aliskiren, 2340 to aliskiren, and 2316 to enalapril. Of these, 1944 (27.7%) had diabetes and 5072 (72.3%) were non-diabetics. The main study results were published in April and showed that aliskiren was not superior or non-inferior to standard treatment with an ACE inhibitor.

Following the results of two separate trials, the EMA requested the withdrawal of all patients with diabetes from ATMOSPHERE. The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) had been stopped after patients with diabetes and a high risk of cardiovascular events were found to have an excess risk of cardiovascular and renal events with aliskiren. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) had found a tendency towards harm in patients with diabetes.

The current study is a prespecified subgroup analysis of ATMOSPHERE according to baseline diabetes status. Due to the premature withdrawal of patients with diabetes from the study drug, median follow-up was shorter in those with diabetes than those without (24.1 months versus 46.0 months; p<0.0001).

The investigators found that the effect of aliskiren on the primary endpoint of cardiovascular death or hospitalisation for heart failure did not significantly differ by baseline diabetes status. In those with diabetes, the primary endpoint occurred in 196 (29.5%) patients in the combination group, compared to 216 (33.1%) in the enalapril group (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.71-1.04; p=0.13), and in 172 (27.4%) patients in the aliskiren group (HR 0.82; 95% CI 0.67-1.00; p=0.053 compared with enalapril).

Regarding the safety of aliskiren in patients with diabetes, compared with enalapril it was associated with a lower risk of symptomatic hypotension (6.7% versus 10.0%; p=0.04). Other adverse events were evenly distributed.

Professor Kober said: "Aliskiren monotherapy looked promising in heart failure patients with diabetes, with an 18% almost significant reduction in cardiovascular death or heart failure hospitalisation compared to enalapril. There was a lower rate of symptomatic hypotension and no increase in other adverse events. This suggests that aliskiren could be an alternative for patients who cannot tolerate an ACE inhibitor."

Combination therapy with aliskiren and enalapril was associated with more adverse events compared with enalapril alone. As the two drugs together did not produce a better outcome, the trial does not support the combination of an ACE inhibitor and aliskiren.

Professor Kober said: "We did a rigorous trial which should have shown that aliskiren is as good as an ACE inhibitor. The drug was never given the chance to demonstrate how good it is because of regulatory interference. That will never be tested now. This could have been a major problem for patients if the neprilysin inhibitor had not emerged."

Antimicrobial agent triclosan can rapidly disrupt gut bacterial communities

In continuation of my update on triclosan

A new study suggests that triclosan, an antimicrobial and antifungal agent found in many consumer products ranging from hand soaps to toys and even toothpaste, can rapidly disrupt bacterial communities found in the gut.

The research was published today [May 18] in PLOS ONE by scientists from Oregon State University. It was based on findings made with zebrafish, which researchers believe are an important animal model to help determine possible human biological and health impacts of this antimicrobial compound.

Triclosan was first used as a hospital scrub in the 1970s and now is one of the most common antimicrobial agents in the world, found in shampoos, deodorants, toothpastes, mouth washes, kitchen utensils, cutting boards, toys, bedding, socks and trash bags. It continues to be used in medical settings, and can be easily absorbed through the skin.

"There has been a legacy of concern about exposure to microbial pathogens, which has led to increased use of these antimicrobial products," said Thomas Sharpton, an assistant professor of microbiology and statistics in the OSU Colleges of Science and Agricultural Sciences, and corresponding author on the new study.

"However, there's now a growing awareness of the importance of the bacteria in our gut microbiome for human health, and the overuse of antibiotics that can lead to the rise of 'superbugs.' There are consequences to constantly trying to kill the bacteria in the world around us, aspects we're just beginning to understand."

In the new study, researchers found that triclosan exposure caused rapid changes in both the diversity and composition of the microbiome in the laboratory animals. It's not clear what the implication may be for animal or human health, but scientists believe that compromising of the bacteria in the intestinal tract may contribute to the development or severity of disease.

 triclosan

Some bacteria were more susceptible to the impact of triclosan than others, such as the family Enterobacteriaceae; and others were more resilient, such as the genus Pseudomonas.

"Clearly there may be situations where antibacterial agents are needed," said Christopher Gaulke, lead author on the study and a postdoctoral microbiology researcher in the OSU College of Science.

"However, scientists now have evidence that intestinal bacteria may have metabolic, cardiovascular, autoimmune and neurological impacts, and concerns about overuse of these agents are valid. Cumulative impacts are also possible. We need to do significantly more evaluation of their effects, some of which might be dramatic and long lasting."

The gut-associated microbiome performs vital functions for human health, prevents colonization with pathogens, stimulates the development of the immune system, and produces micronutrients needed by the host. Dysfunction of this microbiome has been associated with human disease, including diabetes, heart disease, arthritis and malnutrition, the scientists pointed out in their study.

Humans are routinely exposed to an array of chemicals, metals, preservatives, microbes and nutrients, some of which may be beneficial, some innocuous, and others harmful, the researchers said. Part of the strength of the present study is developing improved ways, through rapid screening of zebrafish, to more easily determine which compounds may be acceptable and which are toxic, scientists say.

Triclosan has been a concern in part because it is so widely used, and it's also readily absorbed through the skin and gastrointestinal tracts, showing up in urine, feces and breast milk. It also has been associated with endocrine disruption in fish and rats, may act as a liver tumor promoter, and can alter inflammatory responses.

This study showed it was quickly associated with shifts in the microbial community structure and can alter the abundance of specific taxa.

Benefits of consuming dried fruits and nuts

A 2015 study observed that tree nut intake was associated with a decrease in total cholesterol, LDL, "bad", cholesterol and triglycerides. It also asserted that nut consumption in general, rather than just a specific type, was the major reason for the decrease.

Weight Control

Nuts not only offer nutritional benefits, but may help to control body weight. This is important as obesity rates continue to rise across developed nations. While nuts have a high energy content, several studies found that frequent nut consumption was not associated with a higher body mass index. In fact, long-term nut consumption is associated with lower weight gain and overweight/obesity.

Type 2 Diabetes

Some studies have investigated the effect of nut consumption on diabetes risk. A 2011 PREDIMED study observed a 52% reduction in diabetes incidence in two experimental groups supplemented with olive oil or 30 g (1 oz) of nuts (a mix of walnuts, almonds and hazelnuts) per day, compared with the control group.

Research suggests that dried fruit consumption is also good for people who have diabetes. A 2015 study observed that consuming raisins as an alternative to processed snacks resulted in a 23% reduction in postprandial glucose levels.

Gastrointestinal Function

Dried fruits are well-known sources of dietary fiber, which has a direct effect on gastrointestinal function. In 2013, prunes were granted a specific EU health claim for their contribution to digestive health. Eating 100 g of prunes (3.5 oz, 8-12 pieces) daily promotes good digestive health and provides more than 19% of the daily recommended intake of fiber.

Osteoporosis

Among nutritional factors, recent observations suggest that prunes may be helpful in both preventing and reversing bone loss. A 2011 study suggests that prunes may improve the bone mineral density in postmenopausal women.

Phase I study of triple drug combination shows promise in multiple myeloma patients

In continuation of my updates on Dexamethasone,  Plitidepsin and  Bortezomib 

Dexamethasone    Plitidepsin

 Bortezomib 

PharmaMar (MSE:PHM) announces the positive results from a Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Dr María Victoria Mateos, MD of the Hematological Department of the University Hospital of Salamanca, Spain, the principal investigator of the study, will present the results in an oral session on June 3rd, 2016 during the 52nd Congress of the American Society of the Clinical Oncology (ASCO), taking place in Chicago (USA), June 3 - 7.

The primary objective of this 20-patient study was to identify the recommended dose for the triple combination (dexamethasone / bortezomib / plitidepsin) administered every four weeks. Efficacy and the safety profile were also evaluated. The overall response rate (ORR) was 56%, including very good partial responses (VGPR) in 33% of the patients and a remarkable partial remission in one triple refractory patient. The median progression free survival (PFS) was 8.3 months. Additionally, 90% of the patients showed a DOR of 6 months or more and clinical benefit was observed in 72% of the patients.

Dose limiting toxicities were not seen in any of the evaluated patients; therefore, the full dose of plitidepsin and bortezomib when used alone were established as the recommended dose for the triple combination. The treatment was well tolerated. The hematological toxicity was manageable and the non-hematological toxicity was in general mild, with the exception of one case of creatinine increase.

Out of the 20 patients that participated in the study, 10 are still under the treatment. The median age was 65. All patients had relapsed after previously receiving, on average, 3.5 therapeutic regimens (range 1-10). Forty-five percent of these patients had been subject to a hematopoietic stem cell transplant (8 autologous, 1 allogeneic). Of the 18 patients evaluable for efficacy, 83% (15 patients) had previously received bortezomib and lenalidomide. One was refractory to bortezomib and seven to lenalidomide.

In abstract #8006, Dr María Victoria Mateos and her team explain that despite the recent progress in the treatment of multiple myeloma due to the introduction of proteasome inhibitors (PIs), the new immunomodulatory drugs (IMIDs), and monoclonal antibodies, the illness is still incurable. Therefore, active compounds with novel mechanisms of action and adequate safety profile are needed. Plitidepsin targets the eukaryotic Elongation Factor eEF1A2, an overexpressed protein in multiple myeloma that contributes to its pathogenesis. The positive results from this study will be added to the already extensive data package from Phase II and Phase III trials, where plitidepsin has shown activity and a favorable safety profile in combination with dexamethasone.

DECT trial shows combination of epirubicin and trastuzumab improves outcomes in breast cancer patients

In continuation of my update on epirubicin 

The study entitled "A phase II neoadjuvant sequential regimen of docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab. The DECT trial" has recently appeared in the Journal of Cell Physiology, an international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research of Philadelphia, Temple University Pennsylvania, USA and the Department of Medicine Surgery and Neuroscience at University of Siena.

 epirubicin

"The use of trastuzumab, a monoclonal antibody targeting the HER2 receptor, has dramatically improved the prognosis of the subgroup of breast cancer patients whose tumors overexpress this specific receptor. One of the greatest challenges in these patients has been combining trastuzumab with extremely effective drugs such as anthracyclines at the cost of an acceptable toxicity. Initial evidence seemed to discourage this approach due to the high-rate of cardiotoxicity, i.e., 27%, reported in the pivotal phase III trial of metastatic breast cancer from Slamon and colleagues. Subsequent studies have partly downsized these results. Yet, several doubts have remained concerning the combined use of these drugs. The DECT trial was design to further address this key question. We also used the data from this randomized trial to interpret treatment efficacy in light of hormonal and metabolic determinants, including the expression of estrogen and progesterone receptors and body mass index," says Prof. Antonio Giordano.

"We enrolled 45 HER2-positive breast cancer patients with locally advanced or operable HER2-positive disease to test the efficacy and toxicity of epirubicin combined with trastuzumab. We observed an exceptionally high rate of responses, particularly in the subgroup of patients with inflammatory disease, and no relevant toxicity, including cardiotoxicity. In addition, some specific disease-and patient-related features were associated with better outcomes. More specifically, the highest chances of optimal response were associated with the lack of hormone receptors and higher BMI," says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome.

"Although current guidelines discourage from the concurrent use of trastuzumab and anthracyclines in HER2-positive breast cancer, we challenged once more the available evidence by administering a less cardiotoxic anthracycline, i.e., epirubicin at a high dose. The results obtained were remarkable in terms of efficacy and absolutely encouraging in terms of toxicity. In addition, our finding on BMI may deserve further investigation in future studies of HER2-positive breast cancer. The goal we pursue is to define the HER2-positive patient profile which better matches with the highest efficacy at the price of an absolutely acceptable toxicity, including cardiotoxicity," clarifies and concludes Prof. Giordano, a renowned expert in breast cancer.

Investigational drug abemaciclib shows durable clinical activity for variety of cancer types

In continuation of my  updates on palbociclib (Ibrance)  and letrozole

Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.

Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.

  letrozole  palbociclib

The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.

 abemaciclib

How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.

In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.

Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.

Author Comment: "These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers," said Shapiro.

"The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer," added Patnaik.

Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.

Maternal pregabalin exposure linked to major birth defect risk

 

In continuation of my update on Pregabalin 

First trimester exposure to pregabalin may be associated with an increased risk of major birth defects (MBDs), an observational study suggests.

The data from eight Teratology Information Services in seven countries on 164 exposed pregnancies showed that the risk of MBDs was increased a significant threefold compared with 656 unexposed pregnancies.

After limiting the findings to just first trimester exposure and excluding chromosomal aberration syndromes, the rate of major congenitalmal formations was 6.0% among 116 infants exposed to pregabalin as neonates versus 2.1% among 580 unexposed infants. These included four chromosomal and eight structural anomalies affecting the central nervous system (CNS), or the skeletal, cardiac, and skin or vascular systems.

"Our results raise a signal for a possible increase in the rate of MBD after pregabalin treatment during the first trimester of pregnancy", say researcher Ursula Winterfield (Centre Hospitalier Universitaire
Vaudois, Lausanne, Switzerland) and colleagues.

The rate of CNS malformations alone was also significantly higher following pregabalin exposure, increased sixfold, at 3.2% compared with  0.5%.

The researchers note that in all four cases of CNS malformations, the mother had been concurrently taking other substances during pregnancy  in addition to pregabalin and genetic causes have not been ruled out,  but they add: "[G]iven that pregabalin is a centrally acting agent, the possibility that these findings may signal a teratogenic effect in humans needs to be considered."

Other secondary outcomes included rates of live births, spontaneous abortions, preterm deliveries and delivery gestational age and birth weight. Of these, only the rate of live births was lower in the pregabalin-exposed group and this was primarily due to a higher rate of elective and medically indicated pregnancy terminations, suggestive of unplanned pregnancies.

Women were mainly taking pregabalin to treat neuropathic pain, but other indications included psychiatric disorders, epilepsy and restless leg syndrome.

The average daily dose of pregabalin was 150 mg; 77% of women started treatment before becoming pregnant and discontinued at a median  gestational age of 6 weeks. However, more than half of the patients continued treatment beyond this point and 33% beyond 7 weeks. First trimester pregabalin exposure occurred in 96% of patients.

Winterfield and colleagues acknowledge in Neurology that the small sample size and differences across groups in maternal conditions and exposure to concomitant medication mean definitive conclusions cannot be drawn from their findings.

But despite these limitations, Page Pennell (Harvard Medical School, Boston, Massachusetts, USA) and Kimford Meador (Stanford University School of Medicine, Palo Alto, California, USA) say in a related editorial that "this study reflects the prescribing pattern for pregabalin".

They recommend: "Each woman receiving a prescription for a neuropsychiatric indication should receive counselling about the potential risk-benefit ratio for her individually, effective birth control until pregnancy is desired, and increased monitoring during pregnancy and for her child through early neurodevelopment."

Ref : http://www.neurology.org/content/early/2016/05/18/WNL.0000000000002780

Flavopiridol drug could be effective strategy to impair brain cancer growth

Glioblastoma, the most common form of brain cancer is a deadly disease for which at present there is no cure. Now, researchers have
published research results that show how re   purposing the  old drug
flavopiridol could be an effective strategy to cut short sugar availability and impair cancer growth.

One of the most remarkable feature of glioblastoma cells is their ability to reprogram their metabolism switching towards a glycolytic energetic metabolism, which relies on high glucose uptake and consumption to sustain the cancer cell's malignant activities. However, because flavopiridol, a synthetic flavonoid already used in the past against cancer, inactivates the enzyme glycogen phosphorylase, this metabolic switching could be used as a therapeutic target. The authors set out to test whether flavopiridol could be used to restrain glioblastoma cell growth by decreasing the availability of glucose as substrate for the glycolytic process, cutting off the tumor's energy supply.

The results, published on the Journal of Cellular Physiology, comes from the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University and the University of L'Aquila and Siena in Italy.

The ability of Flavopiridol to reduce glycolisys in glioblastoma cells and inhibit their proliferation is a significant step toward deriving new treatments for what is currently an incurable form of cancer. According to Annamaria Cimini of the University of L'Aquila, lead author of the study, "This points toward a possible new use of this compound or flavopiridol-derived formulations in combination with
anti-proliferative agents in glioblastoma patients."

"The design of new flavopiridol-based formulations, aimed at starving cancer cells cutting short the sugar they're addicted to, may open up new therapeutic avenues for patients with glioblastoma," says Antonio Giordano, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology at Temple University in Philadelphia, PA USA in collaboration with the Department of Medicine, Surgery & Neuroscience at the University of Siena, and University of L' Aquila Italy.

 Ref : https://shrodotorg.wordpress.com/2016/05/20/old-drug-could-fight-brain-cancer-by-starving-it-to-death/