Researchers find promising drugs that could lead to first antidote for radiation exposure

University of Virginia School of Medicine researchers have identified promising drugs that could lead to the first antidote for radiation exposure that might result from a dirty bomb terror attack or a nuclear accident such as Chernobyl.

Some of the compounds, including the drug rapamycin, have previously been shown toextend life in organisms such as worms and flies, though it's unknown if they would have the same benefit in humans. UVA's research suggests that these compounds, or similar drugs, might counter the deadly effects of ionizing radiation.

 rapamycin

Currently there is no treatment for people exposed to lethal doses of radiation; doctors can only try to ease their suffering until death. "If you're exposed to a very, very high dose, it's rapid deterioration and immediate death," explained John S. Lazo, PhD, of UVA's Department of Pharmacology. "It's the lower doses that people - particularly governments - are concerned about. The type of exposure that might result from a dirty bomb or a nuclear accident. How do we alleviate the effects? What's the antidote? Right now, we just don't have anything."

Innovative Approach

Lazo and his colleague Elizabeth R. Sharlow, PhD, screened a library of more than 3,400 existing drugs, vitamins and other compounds to identify ones that might help cells withstand the effects of radiation exposure. The goal was to keep stem cells - the cells that produce the various cell types in the body - alive long enough to repair the damage caused by radiation.

"We wanted to find already approved drugs that would potentially keep stem cells, or progenitor cells, alive after radiation exposure," Sharlow said. "That's very much of interest to the NIH [National Institutes of Health] right now: How can we keep those se

lf-renewing populations alive so they can actually help heal the effects of radiation exposure?"

After they identified potential leads, Sharlow created 3D computer models to compare the substances' chemical structures. That analysis identified a cluster of promising compounds with similar structures - a tantalizing lead in the quest for an antidote. "If you're a drug hunter, the way we are, this is really cool information," Lazo said. "Because you can say, 'Now I will look in the universe of 40 million compounds. What else looks like that? Are they useful?'"

He noted that it is unlikely any one drug or compound will work on its own. "A lot of us in this field think it will be a cocktail of things you take," he said. "And if you think you need cocktails, you need the individual ingredients. That's why we think this is pretty important - because it's providing new ingredients for that cocktail."

Natural molecule NAC could benefit patients with Parkinson's disease

The natural molecule, n-acetylcysteine (NAC), with strong antioxidant effects, shows potential benefit as part of the management for patients with Parkinson's disease, according to a study published today in the journal PLOS ONE. Combining clinical evaluations of a patient's mental and physical abilities with brain imaging studies that tracked the levels of dopamine, the lack of which is thought to cause Parkinson's, doctors from the Departments of Integrative Medicine, Neurology, and Radiology, at Thomas Jefferson University showed that patients receiving NAC improved on both measures.

 Acetylcysteine

Current treatments for Parkinson's disease are generally limited to temporarily replacing dopamine in the brain as well as some medications designed to slow the progression of the disease process. Recently, researchers have shown that oxidative stress in the brain may play a critical role in the Parkinson's disease process, and that this stress also lowers levels of glutathione, a chemical produced by the brain to counteract oxidative stress. Studies in brain cells showed that NAC helps reduce oxidative damage to neurons by helping restore the levels of the antioxidant glutathione. NAC is an oral supplement that can be obtained at most nutrition stores, and interestingly also comes in an intravenous form which is used to protect the liver in acetaminophen overdose.

"This study reveals a potentially new avenue for managing Parkinson's patients and shows that n-acetylcysteine may have a unique physiological effect that alters the disease process and enables dopamine neurons to recover some function," said senior author on the paper Daniel Monti, M.D., M.B.A., Director of the Myrna Brind Center of Integrative Medicine, and the Brind-Marcus Center of Integrative Medicine at Thomas Jefferson University.

In this study, Parkinson's patients who continued their current standard of care treatment, were placed into two groups. The first group received a combination of oral and intravenous (IV) NAC for three months. These patients received 50mg/kg NAC intravenously once per week and 600mg NAC orally 2x per day on the non IV days. The second group, the control patients, received only their standard of care for Parkinson's treatment. Patients were evaluated initially, before starting the NAC and then after three months of receiving the NAC while the control patients were simply evaluated initially and three months later. The evaluation consisted of standard clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS), a survey administered by doctors to help determine the stage of disease, and a brain scan via DaTscan SPECT imaging, which measures the amount of dopamine transporter in the basal ganglia, the area most affected by the Parkinson's disease process. Compared to controls, the patients receiving NAC had improvements of 4-9 percent in dopamine transporter binding and also had improvements in their UPDRS score of about 13 percent.

"We have not previously seen an intervention for Parkinson's disease have this kind of effect on the brain," said first author and neuro-imaging expert Andrew Newberg, M.D., Professor at the Sidney Kimmel Medical College at Jefferson and Director of Research at the Myrna Brind Center of Integrative Medicine. The investigators hope that this research will open up new avenues of treatment for Parkinson's disease patients.

Rice University researchers synthesize new anti-cancer agent

Rice University scientists have synthesized a novel anti-cancer agent, Thailanstatin A, which was originally isolated from a bacterial species collected in Thailand.

 

Thailanstatin A

Thailanstatin A fights cancer by inhibiting the spliceosome, the machinery in the cell that edits messenger RNA after transcription from DNA but before its translation into proteins.

Rice synthetic chemist K.C. Nicolaou and his group reported their success in the Journal of the American Chemical Society.

Nicolaou and his colleagues specialize in the synthesis of potential therapeutic agents that are found in nature but in amounts too small for thorough biological evaluation or clinical use. He is best known for the total synthesis of paclitaxel, a drug commonly used to treat a number of cancers.

The researchers explained that the spliceosome, a complex of proteins and ribonucleoproteins that regulate DNA splicing, is more active and displays higher mutation rates in cancer cells than in healthy cells, which makes it a valid target for investigation.

"This cellular machinery edits mRNA as it emerges from the transcription of DNA through site-specific removal of introns (noncoding regions of DNA) and splicing the remaining exon (coding) sequences prior to translation," Nicolaou said. "Thailanstatin A interferes with this mechanism."

He said the synthesis of Thailanstatin A, first isolated from burkholderia thailandensis bacteria, opens the way to construct and test variations of the molecule. "These studies will be directed toward optimization of the pharmacological properties of this new natural product as part of a drug discovery and development program targeting new therapies for cancer," Nicolaou said.

The program can take two directions, he said: one directed toward high-potency compounds that could be used as payloads for antibody drug conjugates and the other toward selective agents that can kill cancer cells with minimal damage to healthy cells.

The first paradigm is currently a frontier approach for the development of targeted and personalized cancer therapies, while the second represents a more traditional approach that could also lead to powerful anti-cancer drugs, Nicolaou said. "Thailanstatin A exhibits just the right potency to be diverted to either approach through a reiterative molecular design, chemical synthesis and biological evaluation process," he said.

"We're excited about this new molecule and its analogs because of their unique biological properties and the prospects of working collaboratively with industrial and academic partners to advance them toward the clinic," Nicolaou said.

Rice University researchers synthesize new anti-cancer agent

Clinical trial finds pioglitazone drug safe and effective for NASH patients

In continuation of my update on Pioglitazone

Researchers have found that an existing diabetes drug can be used to halt progression of another disease that is a leading cause of liver transplants.

A three-year clinical trial led by University of Florida Health researcher Kenneth Cusi, M.D., found that the drug pioglitazone is safe and effective in certain patients who have nonalcoholic steatohepatitis, or NASH, a chronic liver disease caused by a buildup of fat. The findings are published today (June 20) in the journal Annals of Internal Medicine.

NASH is often known as "silent" liver disease and affects 10 to 20 percent of the population and perhaps as many as one-third of all patients with adult-onset diabetes in the United States, according to recent studies. Left unchecked, NASH can cause chronic inflammation that leads to liver cancer or cirrhosis. NASH is now the second-leading cause of liver transplants and the numbers continue to grow each year, said Cusi, chief of the division of endocrinology, diabetes and metabolism in the UF College of Medicine's department of medicine.

Early diagnosis and treatment of NASH is crucial for those who are at greatest risk for the disease, usually obese patients who also have prediabetes or Type 2 diabetes. But until now, Cusi said, there was little urgency to diagnose NASH because there were no available medications.

The research group's single-center clinical trial involving 101 NASH patients with prediabetes or Type 2 diabetes found that pioglitazone reduced fatty liver disease activity in 58 percent of participants. In just more than half the participants -- 51 percent -- the disease was reduced enough that it was no longer considered a threat to the liver.

"The exciting thing is that there is a generic drug that already prevents the onset of Type 2 diabetes and cardiovascular disease in recent studies. Now, it can reduce disease from excess liver fat accumulation and liver inflammation, and halt fibrosis that leads to cirrhosis. This will have a lot of long-term benefits for many people with a medication that will be very affordable and is already being used to treat Type 2 diabetes," Cusi said.

The study also has implications for people with prediabetes and NASH because fatty liver disease is a risk factor for Type 2 diabetes even in those who aren't obese, researchers said.

Federal regulators approved Actos (pioglitazone) in 2000 and a generic version of the drug in 2012 to improve blood glucose control in adults with Type 2 diabetes. Still, pioglitazone's use against liver disease will require a larger, multicenter clinical trial that could take seven years or more in addition to U.S. Food and Drug Administration approval. A multicenter trial would allow researchers to learn more about the drug's long-term benefits for liver issues and determine why some participants respond better than others to the medication, Cusi said.

Researchers aren't entirely certain about how pioglitazone works against liver disease. Patients with NASH are insulin-resistant, meaning their body does not respond normally to their own insulin. This defect promotes fat accumulation and inflammation in the liver. The researchers believe the medication makes molecular improvements in the liver and other tissues such as fat. That helps the body's response to insulin, making it insulin-sensitive again and restoring normal metabolism.

Despite the recent trial's relatively small size, Cusi noted that it's the largest single-center study and the first long-term study examining the drug as treatment for people who have NASH along with prediabetes or Type 2 diabetes. It is also the longest NASH-related study with any drug and had the greatest treatment effect on NASH compared with other approaches, he said.

Apixaban effective in polypharmacy setting

In continuation of my update on Apixaban

The superiority of apixaban over warfarin in patients with atrial fibrillation is maintained in those taking multiple medications, shows further analysis of the ARISTOTLE trial.

 Apixaban

The researchers found superior efficacy of apixaban against the primary thromboembolic endpoint (stroke or systemic embolism) regardless of the number of drugs patients were taking.

By contrast, the advantage of apixaban over warfarin in terms of major bleeding tended to decline in line with the number of drugs patients were taking. The absolute rate reduction per 100 patient-years with apixaban versus warfarin was 1.28 for patients taking up to five medications, falling to 0.82 and 0.66 for those taking six to eight and more than nine drugs, respectively.

"Importantly, the risk reduction of intracranial bleeding did not diminish with an increasing number of concomitant drugs", write the researchers in The BMJ.

"Therefore, the fact that the relative benefit of apixaban over warfarin appears to diminish across groups is due to other types of major bleeding."

They give the example of major gastrointestinal bleeding, which was significantly reduced with apixaban versus warfarin in patients taking up to five drugs, but not in those taking nine or more drugs.

Polypharmacy was common among the 18,201 ARISTOTLE participants, with 76.5% taking at least five concomitant drugs. Patients' average age rose in line with the number of drugs used, as did their stroke and bleeding risk. Patients taking more drugs also had more cardiovascular comorbidities, and also more neurological, renal, endocrine, musculoskeletal, pulmonary, gastrointestinal and haematological comorbidities.

Rates of the primary thromboembolic and bleeding endpoints rose with the number of drugs taken for patients in the apixaban group as well as those in the warfarin group.

Jeroen Jaspers Focks (Radboud University Nijmegen Medical Centre, the Netherlands) and study co-authors stress that "this increased risk of adverse outcomes should be placed in the context of the association between the number of drug treatments and comorbidities present at baseline, indicating a more frail status of patients with polypharmacy."

The researchers suggest that adjusting for these differences would abolish the relationship between the number of drugs used and safety outcomes, but add that the purpose of the study was to use polypharmacy as a marker of patient frailty.

Moreover, increasing frailty did not significantly influence the efficacy of apixaban against stroke or systemic embolism, with the relative risk versus warfarin being 14% among those taking up to five drugs and 24% in those taking more.

Espero Pharmaceuticals Receives FDA Approval for GoNitro (nitroglycerin) Sublingual Powder

Espero Pharmaceuticals, Inc., a privately held specialty pharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved GoNitro (nitroglycerin) sublingual powder for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. With this approval, GoNitro is the first and only short-acting nitrate in a stabilized crystal granule form available in single dose packets.

“The FDA’s approval of GoNitro enhances the treatment options available to the more than 8 million U.S. patients suffering with stable angina due to coronary artery disease (CAD), the most common type of heart disease,” commented Quang Pham, Founder and CEO of Espero Pharmaceuticals. “GoNitro is a sublingual nitrate and as this class of drug therapy is a Class I recommendation according to the 2012 Stable Ischemic Heart Disease (SIHD) Guidelines, it should be prescribed to all patients with known SIHD.”

“Short-acting nitrates are the current standard of care for acute relief of an angina attack. The novel features of a sublingual powder in a portable single dose packet make GoNitro attractive to angina patients who need fast relief and want to continue to live an active lifestyle,” said Dr. A. Allen Seals, Fellow of the American College of Cardiology (FACC).

Each individual packet of GoNitro contains 400 mcg of nitroglycerin. The clinical data indicate that the sublingual absorption of nitroglycerin is higher following the administration of GoNitro compared to Nitrolingual® Pumpspray (nitroglycerin lingual spray) which was launched in 1997 and is currently marketed by Espero in the U.S. GoNitro was approved by the FDA via the 505(b) regulatory pathway.

Espero will promote and distribute GoNitro nitroglycerin sublingual powder in the U.S. market under an exclusive licensing agreement with G. Pohl-Boskamp GmbH & Co. KG, (Pohl Boskamp), an established global leader in the short-acting nitrate market. The United States Patent and Trademark Office awarded Pohl Boskamp Patent No. 9,101,592 B2 for stabilized granules containing glyceryl trinitrate (GTN or nitroglycerin) in August 2015.

“GoNitro is the first new dosage form in the short-acting nitrate category in nearly 20 years and we intend to educate healthcare providers and patients about our exciting new product immediately,” remarked Jeff Cole, President & CFO of Espero Pharmaceuticals.

GoNitro will be available in the second half of 2016 and promoted by Espero’s specialty sales force at launch.




Cabozantinib extends advanced RCC overall survival

In continuation of my update on Cabozantinib

Patients with advanced or metastatic renal cell carcinoma (RCC) derive a significant overall survival (OS) benefit from second-line treatment with the multi-tyrosine kinase inhibitor (TKI) cabozantinib relative to everolimus.

These findings come from the final analysis of the phase III METEOR trial in which 330 participants were randomly assigned to receive cabozantinib 60 mg/day and 328 allocated to the mammalian target of rapamycin inhibitor everolimus at a dose of 10 mg/day. All patients had received at least one previous vascular endothelial growth factor receptor TKI.

After a median follow-up of 18.7 and 18.8 months in the cabozantinib and everolimus arms, respectively, the corresponding median OS times were 21.4 and 16.5 months, a significant difference equating to a hazard ratio for death of 0.66.

Progression-free survival was also significantly improved in the cabozantinib arm, as was the objective response rate - findings that were consistent with the previously reported results for the first 375 randomly assigned patients, report Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and team.

They conclude in The Lancet Oncology: "Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma."

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

Ref : http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2816%2930107-3/abstract

Carfilzomib therapy shows promise for pre-kidney transplant patients

In continuation of my update on carfilzomib,

Early findings by researchers at the University of Cincinnati (UC) College of Medicine suggest that the use of a second generation cancer drug, carfilzomib, may provide an improved approach for the reduction of antibodies in potential kidney transplant candidates. The research team includes members from UC Transplant Clinical Research, UC's Division of Hematology Oncology and the Cincinnati Children's Hospital Medical Center's Biomedical Informatics division.

 carfilzomib

This pre-transplant drug therapy approach is aimed at reducing antibodies in kidney transplant candidates with greater success than with traditional methods and with reduced side effects.

Antibodies are Y-shaped proteins that in most instances are good because they help fight infection, but people can also make antibodies that work against other humans, which is often a major barrier to transplantation.

"Carfilzomib has been well tolerated by the first group of six study patients who experienced antibody reductions between 31 to 100 percent," says the study's lead author Simon Tremblay, PharmD, research associate in the UC College of Medicine's transplant research programs.

The study's preliminary findings will be presented at the annual American Transplant Congress on June 13, in Boston, Mass., where Tremblay will be awarded the American Transplant Society's Young Investigator award.

Since 2008, the UC research team has been developing therapies that target plasma cells—the cells that make antibodies. The first generation of drug therapy studied was the cancer drug bortezomib, a proteasome inhibitor that, like carfilzomib, is already approved by the Food and Drug Administration for treatment of multiple myeloma. In that 50 person study, which was published in 2015, a significant decrease in antibodies was observed. Furthermore, transplanted patients had low rejection rates and the chances of developing a new antibody against their kidney was also low. In addition, in some patients, antibodies remained suppressed for several months—something that has not previously been described with other approaches.

In the same scientific session, James Driscoll, MD, PhD, assistant professor in the UC College of Medicine's Division of Hematology Oncology, will present the results of translational research studies in the carfilzomib-treated patients. Driscoll will present new genomic data on plasma cells isolated from patients prior to and after receiving carfilzomib therapy.

"Our gene expression profiling studies in normal human plasma cells are giving us a detailed, comprehensive view of how plasma cells survive and avoid the death inducing effects of carfilzomib," says Driscoll. These studies, he says, were performed in collaboration with Bruce Aronow, PhD, at Cincinnati Children's.

Carfilzomib is one of four new regimens—described as "second-generation plasma cell targeted therapies that are being evaluated by the UC transplant Clinical Research Team, " says the principal investigator on both studies, E. Steve Woodle, MD, UC Health transplant surgeon and director of the division of transplantation at the UC College of Medicine.

New experimental antibiotic can help combat MRSA infections

A new experimental antibiotic developed by a team of scientists at Rutgers University successfully treats the deadly MRSA infection and restores the efficacy of a commonly prescribed antibiotic that has become ineffective against MRSA.

In research published in the July issue of Antimicrobial Agents and Chemotherapy, Rutgers scientists say that the combination of their newly developed antibiotic, TXA709, with cefdinir, an antibiotic that has been on the market for almost two decades, successfully treated the MRSA infection in animals.

"This is important because even though TXA709 is effective on its own in treating MRSA, combining it with cefdinir - used to treat a wide range of bacterial infections like strep throat, pneumonia, bronchitis and middle ear and sinus infections - makes it even more efficacious, while also significantly reducing the potential for the MRSA bacteria to become resistant in the future," said Daniel Pilch, associate professor in the Department of Pharmacology at Robert Wood Johnson Medical School.

Pilch and fellow scientists are racing to develop a new class of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) infections, which are responsible for 19,000 deaths annually and represent $3 billion in annual health care costs.

The threat of MRSA and other antibiotic-resistant infections has become so severe that the World Health Organization predicts that common infections and minor injuries could become life-threatening because of a lack of drug treatments available to destroy these bacterial infections. Last month the first case in the United States of a patient with an infection resistant to all known antibiotics was reported by the U.S. Centers for Disease Control and Prevention.

"Current standard-of-care drugs for the treatment of MRSA infections are limited," said Pilch. "Furthermore, resistance to these drugs is on the rise, and their clinical effectiveness is likely to diminish in the future."

Pilch said that TXA709 kills MRSA bacteria in a unique manner unlike any other antibiotic in current clinical use, inhibiting the function of a protein, FtsZ, essential for the bacteria to divide and survive. By combining TXA709 with cefdinir, a cephalosporin antibiotic that acts much like penicillin, scientists were able to lower the dosage of the new antibiotic required to eradicate the MRSA infection.

This is significant, Rutgers scientists say, because it decreases the potential for any drug-induced toxicity and side effects that might occur from a higher dosage.

"What is also good about this experimental treatment is that both drugs can be taken orally, which means they can be administered on an outpatient basis," said Pilch, who collaborated with Edmond LaVoie, professor and chair of the Department of Medicinal Chemistry at the Ernest Mario School of Pharmacy at Rutgers. "All but two of the current antibiotics being used clinically to treat MRSA need to be administered intravenously," he said.

Researchers say Phase I clinical trials on the new antibiotic, which will assess and evaluate its safety and effectiveness in humans, are expected to begin next spring.

Ref : http://aac.asm.org/content/59/8/4845.full?sid=949e5603-f4b2-4eec-8e5f-f79d0c758e44

Empagliflozin offers long-term renal protection in Type 2 diabetes

The sodium-glucose cotransporter 2 inhibitor empagliflozin slows renal progression and averts clinical events, shows further analysis of the EMPA-REG OUTCOME trial.

 empagliflozin 

The previously reported primary analysis showed a reduced risk of major cardiovascular events in patients randomly assigned to take empagliflozin 10 or 25 mg daily, compared with placebo, in addition to their existing medication.

As now reported in The New England Journal of Medicine, the researchers found that microvascular events were also significantly less common in the 4132 patients taking either empagliflozin dose than in the 2068 taking placebo, at 14.0% versus 20.5%.

This was driven almost entirely by renal outcomes, report Christoph Wanner (Würzburg University Clinic, Germany) and team.

Incident or worsening nephropathy occurred in 12.7% of the empagliflozin group versus 18.8% of the placebo group, a significant 39% relative reduction. And 11.2% of patients taking empagliflozin versus 16.2% of those taking placebo progressed to macroalbuminuria, equating to a significant 38% risk reduction.

Patients in the empagliflozin group also had a significantly reduced risk of having a doubling of their serum creatinine level and requiring initiation of renal-replacement therapy.

During the first 4 weeks of treatment, patients taking empagliflozin had a reduction in their average estimated glomerular filtration rate (eGFR) of 0.62 and 0.82 mL/min per 1.73 m2 in the 10 and 25 mg dose groups, respectively. After this, however, eGFR in both groups remained relatively stable, with an annual decline of just 0.19 mL/min per 1.73 m2, compared with 1.67 mL/min per 1.73 m2 in the placebo group.

In an editorial that also refers to the just published LEADER trial, Julie Ingelfinger (Massachusetts General Hospital, Boston, USA) and Clifford Rosen (Maine Medical Center Research Institute, Scarborough, USA) agree with the LEADER investigators' view that differences in trial design and participant characteristics do not account for diabetes medications being cardioprotective in some studies but not others.

"We are left with differences that appear encouraging, yet are not a 'home run' with regard to the management of diabetes", they write.

The editorialists hope that, in the future, head-to-head trials of older and newer diabetes therapies "may help to delineate an even more effective treatment plan for the millions of people whose lives are affected by type 2 diabetes."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1515920#t=abstract

Cranberries can reduce symptomatic UTIs and avoid chronic suppressive antibiotics

 In continuation of my update on craneberries

According to the study, recently published by the American Journal of Clinical Nutrition, drinking an 8-ounce (240 ml) glass of cranberry juice a day reduces symptomatic UTIs by nearly 40 percent in women with recurrent UTIs - reducing the burden of UTIs and reducing the antibiotic use associated with treating recurrent UTIs.

"Currently the primary approach to reducing symptomatic events of UTI is the use of chronic antibiotics for suppression, an approach associated with side effects and development of antibiotic resistance. This study shows that consuming one 8-ounce (240 ml) glass of cranberry juice a day reduces the number of times women suffer from repeat episodes of symptomatic UTI and avoids chronic suppressive antibiotics," said Dr. Kalpana Gupta, infectious disease specialist and Professor of Medicine at Boston University's School of Medicine.

An author on the study and panelist at today's session, Dr. Gupta believes that cranberries can help to reduce the worldwide use of antibiotics and significantly improve the quality of life for women who suffer from recurrent UTI symptoms.

Single Largest Clinical Trial on Cranberries of its Kind

The 24-week study of 373 women, conducted by researchers at Boston University, Biofortis Innovation Services (a division of Merieux Nutrisciences) and 18 clinical sites throughout the US and France, is the largest clinical trial of its kind examining the effects of cranberry juice consumption on UTIs. This trial adds to more than 50 years of cranberry research and supports the cranberry's ability to support urinary tract health and reduce symptomatic UTIs among chronic UTI sufferers.

Researchers set out to find whether recurrent (or repeat) UTI sufferers could be protected from repeat infections by drinking cranberry juice. Participants were all healthy women, with an average age of 40, who had experienced at least two UTIs within the past year. During the study, participants were randomly chosen to drink a daily dose of eight ounces (240 ml) of either cranberry juice or a "placebo" beverage without cranberries.

The rate of UTIs decreased significantly among the cranberry drinkers, with just 39 diagnoses during the six-month study compared with 67 in the placebo group.

Compared to some other studies, this trial had greater statistical power to detect differences than others due to its larger sample, use of incidence density to account for the tendency of clinical UTIs to cluster in time within an individual, a high average level of compliance (98%), and a comparatively large percentage of subjects in each group completing the treatment period (86%).

How Cranberries Work

Luckily, cranberries contain a unique combination of compounds including Type-A PACs (or proanthocyanidins) that prevent bacteria from sticking and causing infection. In addition to PACs, new studies have revealed a new class of compounds, xyloglucan oligosaccharides, which have similar anti-bacterial properties against E. coli as PACs. This means there are multiple, unique elements within cranberries working hard for your health.

These unique compounds can be found in a variety of products, including cranberry juice cocktail, 100% cranberry juice, light cranberry juice, dried cranberries and cranberry extract; however most of the research surrounding cranberries and UTIs has been conducted using juice.

Cranberries, a Natural Approach to Better Health

The suggestion that a nutritional approach like cranberry juice could reduce antibiotic use is welcome news given the alarming challenge it presents to public health, one that the WHO refers to as one of the greatest challenges to public health today, and that the UK Chancellor of the Exchequer said could become a threat 'greater than cancer'.

According to Gupta, those who suffer from UTIs can feel confident that this nutritional approach is a potential solution - further validating more than 50 years of well-documented cranberry research.

Long-term dasatinib findings support first-line use in CML

In continuation of my update on dasatinib

Final DASISION study findings confirm dasatinib to be an effective, long-term treatment for patients with a new diagnosis of chronic phase-chronic myeloid leukaemia (CP-CML).

 dasatinib

After 5 years, 61% of 259 patients randomly assigned to receive dasatinib 100 mg/day were still taking the tyrosine kinase inhibitor (TKI), while 63% of the 260 patients started on imatinib 400 mg/day continued with their treatment, the investigators report in the Journal of Clinical Oncology.

The primary endpoint of complete cytogenetic response (CCyR) at 5 years had been achieved by 28% of dasatinib-treated patients and 26% of their imatinib-treated counterparts, although the researchers note that these values may have been higher if bone marrow samples had been tested in the patients at the end of the study.

Cumulative 5-year rates of major molecular response (MMR) and molecular responses with a 4.5-log (MR4.5) reduction in BCR-ABL1 transcripts from baseline were also comparable in the dasatinib and imatinib treatment arms, at 76% versus 64%, and 42% versus 33%, respectively, say Jorge Cortes, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Five-year estimated overall survival was 91.0% for the dasatinib group and 90.0% for those given imatinib. And estimated progression-free survival was a corresponding 85.0% and 86.0% with 4.6% and 7.3% of patients transforming to accelerated or blast phase CML during a period of follow-up that continued beyond TKI discontinuation.

In all, 84% of dasatinib-treated patients and 64% of imatinib-treated patients achievedBCR-ABL1 of 10% or less within 3 months of treatment. Compared with patients who did not reach this target, these individuals were more likely to achieve CCyR, MMR and MR4.5over 5 years, had higher rates of overall and progression-free survival, and were less likely to have transformation.

Cortes et al note that no new adverse effects were reported for dasatinib or imatinib by the end of the 5-year study period and just 15% and 11% of adverse effects were grade 3 or 4 in the groups, respectively.

Patients given dasatinib had higher rates of grade 3 or 4 neutropenia (29 vs 24%), anaemia (13 vs 9%) and thrombocytopenia (22 vs 14%) but lower rates of other nonhaematological side effects, except for any grade of pleural effusion (28.0 vs 0.8%). Discontinuation for drug-related side effects occurred in 16% and 7% of dasatinib- and imatinib-treated patients, respectively.

Pulmonary hypertension was reported in 5.0% and 0.4% of the dasatinib and imatinib groups, respectively, with 12 of the 14 diagnoses deemed to be drug related. Arterial ischaemic events were "uncommon" in both groups, affecting 5.0% and 2.0%, respectively.

However, there was a "disproportionate number" of deaths from infection in the dasatinib versus imatinib groups (11 vs 1), with seven deaths reported between 69 days and 4.5 years after dasatinib discontinuation.

"It will be important to prospectively and intentionally look at a possible imbalance in the occurrence of infections and, if present, determine a possible mechanism(s) for dasatinib-related infectious complications", the investigators comment.

"These results suggest that first-line dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed CML-CP", the researchers conclude.

While patients given dasatinib were more likely to achieve early treatment milestones, the authors explain that the high rates of CCyR and overall survival in both treatment arms mean a longer follow-up period and larger study population are likely needed to demonstrate any significant difference in survival between the TKIs.

Diabetes Drug Victoza May Help the Heart: Study

In continuation of my update on liraglutide

The blood sugar-lowering drug Victoza (liraglutide) cuts the risk of heart attack and stroke in type 2 diabetes patients, a new study finds.

Heart disease is the leading cause of death among people with type 2 diabetes, the researchers noted.

The study was funded by the drug's maker, Novo Nordisk, and the U.S. National Institutes of Health. It included more than 9,300 adults from 32 countries who have type 2 diabetes and a high risk of heart disease.

About half took Victoza, while the other half took an inactive placebo. Both groups also took other medications for health problems, such as high blood pressure and high cholesterol, the study authors said.

Tracking patients for three years, the researchers found that compared with patients in the placebo group, people who took Victoza had a 13 percent lower risk of heart attack or stroke. They also had a 22 percent lower risk of death from heart disease; a 15 percent lower risk of death from any cause; and a 22 percent lower risk of new evidence of advanced kidney disease.

Some patients did discontinue the drug due to "gastrointestinal events," according to the report.

The study was presented June 13 at the American Diabetes Association's annual meeting, in New Orleans. It was also published simultaneously in the New England Journal of Medicine.

"I've been excited about liraglutide for a long time because I think it's unique," said study senior author Dr. John Buse. He directs the Diabetes Care Center at the University of North Carolina, Chapel Hill.

"This is the first diabetes drug that has shown across-the-board benefits for cardiovascular diseases, and this suggests it plays a role in treating atherosclerosis [hardening of the arteries], which is what leads to heart attacks and strokes," Buse said in a university news release.

One diabetes expert called the study "encouraging."

Victoza "is a relatively new medication, given by daily injection," said Dr. Allison Reiss, who runs the inflammation laboratory at Winthrop-University Hospital in Mineola, N.Y.

Still, the long-term effectiveness of the drug is unknown, Reiss added. "It will be important to follow these patients over the next few years to see whether [Victoza] benefits continue and to investigate how it is working," she said.

The researchers explained that Victoza is from a newer class of diabetes drugs known as GLP-1 agonists. These medications work in the pancreas to cut the production of an anti-insulin hormone called glucagon. The drugs boost insulin production and help control blood sugar levels.

As a secondary mechanism, Victoza also works on the brain to help lower appetite and boost feelings of "fullness" when eating, Buse's team explained.

Reiss noted that because of this activity, Victoza can help spur weight loss -- and that might be the prime factor driving the improvements in heart health.

Dr. Gerald Bernstein coordinates the Friedman Diabetes Program at Lenox Hill Hospital in New York City. He said that Victoza -- and other drugs in its class -- are being increasingly used, so "decreased cardiovascular risk is an important finding."

FDA Issues Complete Response Letter for Mycapssa New Drug Application

Chiasma, Inc. , a late-stage biopharmaceutical company focused on improving the lives of patients with rare and serious chronic diseases, today announced that it received a Complete Response Letter (CRL) from the United States (U.S.) Food and Drug Administration (FDA) regarding the company’s New Drug Application for Mycapssa (octreotide) capsules for the maintenance treatment of U.S. adult patients with acromegaly. The FDA issues CRLs to indicate that the review cycle for an application is complete and that the application is not ready for approval in its present form. 

Mycapssa, octreotide (RG3806) (formerly Octreolin)

About Mycapssa

Mycapssa is an investigational new oral drug proposed for the maintenance therapy of adult patients with acromegaly. If approved, octreotide capsules may be the first oral somatostatin analog approved for acromegaly. Octreotide capsules have been granted orphan designation in the United States and the European Union for the potential treatment of acromegaly.

Octreotide capsules are an investigational drug that has not been approved for use in any jurisdiction.

About Chiasma

Chiasma is a late-stage biopharmaceutical company focused on improving the lives of patients suffering from orphan diseases by developing and commercializing novel oral forms of therapies that are available today only by injection. The company’s lead product candidate is Mycapssa (octreotide) capsules, an investigational new drug developed with Chiasma’s Transient Permeability Enhancer (TPE®) technology to facilitate gastrointestinal absorption of unmodified drug into the bloodstream safely. Mycapssa is a proposed tradename, and this investigational new drug has not been approved for use in any jurisdiction. Using TPE® technology, Chiasma is evaluating additional proteins, peptides and small molecule drugs that are currently only available by injection but could potentially be converted to oral delivery. TPE® technology is potentially well suited for drugs with chronic indications, where frequent dosing is required and the need for an oral alternative is greatest. Chiasma is a Delaware corporation with a wholly-owned Israeli subsidiary. Mycapssa and TPE® are trademarks of Chiasma.

Cempra Completes NDA Submissions for Solithromycin in the Treatment of Community-Acquired Bacterial Pneumonia

Cempra, Inc.  , a clinical-stage pharmaceutical company focused on developing antibiotics to meet critical medical needs in the treatment of bacterial infectious diseases, announced the completion of its rolling submission of the New Drug Applications (NDA) for solithromycin to the U.S. Food and Drug Administration (FDA) for the treatment of community-acquired bacterial pneumonia (CABP). Based on the Qualified Infectious Disease Product (QIDP) designation by the FDA of solithromycin, Cempra has Priority Review and has been granted Fast Track for both the oral capsule and intravenous formulations for the treatment of CABP, which could result in an FDA decision on solithromycin's NDA within eight months, or by the end of 2016, based on the Prescription Drug User Fee Act (PDUFA) performance goals.

 Solithromycin

"Completion of the rolling submission of our first NDAs during Cempra's ten year anniversary year represents a major milestone for the company and a significant step toward our goal of developing antibiotics to meet the critical medical needs of patients in the treatment of bacterial infectious diseases," stated Prabhavathi Fernandes, Ph.D., president and chief executive officer of Cempra. "We believe the intravenous and capsule formulations will provide dosing flexibility that could lead to fewer hospital admissions, earlier discharge if admitted, and increased treatment of CABP on an outpatient basis. We are confident we have a strong data package for solithromycin."

"The management of CABP remains a challenge to healthcare professionals and I firmly believe that solithromycin has the potential to be a significant part of the treatment of this life threatening illness, given its published clinical efficacy and potential for multiple formulations," stated Thomas M. File, M.D., principal investigator for solithromycin clinical trials, Northeast Ohio Medical University. "Solithromycin's potency, spectrum of activity and tolerability could help to offset the rising problem of bacterial resistance, and it is gratifying to note that patients could be closer to benefiting from this potential new treatment."

The FDA has a 60-day filing review period to determine whether the NDAs are complete and acceptable for filing, and to confirm that Priority Review has been granted. Cempra expects to communicate the agency's decision regarding acceptance of the NDAs and its PDUFA date when it is known. Cempra's submissions in the EU remain on track for completion by the end of June 2016.

About Solithromycin

Solithromycin is a highly potent next-generation macrolide, the first fluoroketolide, which has potent activity against most macrolide-resistant strains. In vitro and in vivo studies have shown potent activity against S. pneumoniae as well as an extended spectrum of activity against CA-MRSA, streptococci, Haemophilus, enterococci, Mycobacterium avium and in animal models of malaria. It is also active against atypical bacteria, such as legionella, chlamydia, mycoplasma and ureaplasma, and against gonococci and other organisms that cause genitourinary tract infections. It is 8-16 times more potent than azithromycin against many bacteria and is active against azithromycin-resistant strains. Solithromycin's activity against resistant strains is driven by its ability to interact with three sites on the bacterial ribosome, compared to one for current macrolides. The binding to bacterial ribosomes and interaction with three ribosomal sites is expected to limit the development of bacterial resistance to solithromycin.