'Mad Cow' discovery points to possible neuron killing mechanism behind alzheimer’s and parkinson’s diseases

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time discovered a killing mechanism that could underpin a range of the most intractable neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS.

The new study, published recently in the journal Brain, revealed the mechanism of toxicity of a misfolded form of the protein that underlies prion diseases, such as bovine spongiform encephalopathy (“mad cow disease”) and its human equivalent, Creutzfeldt-Jakob disease.

Our study reveals a novel mechanism of neuronal death involved in a neurodegenerative protein-misfolding disease,” said Corinne Lasmézas, a TSRI professor who led the study. “Importantly, the death of these cells is preventable. In our study, ailing neurons in culture and in an animal model were completely rescued by treatment, despite the continued presence of the toxic misfolded protein. This work suggests treatment strategies for prion diseases—and possibly other protein misfolding diseases such as Alzheimer’s.

'Mad Cow' discovery points to possible neuron killing mechanism behind alzheimer’s and parkinson’s diseases

Diabetes drug can boost efficacy of TB medication without causing drug resistance

In continuation of my update on Metformin

A more effective treatment for tuberculosis (TB) could soon be available as scientists have discovered that Metformin (MET), a drug for treating diabetes, can also be used to boost the efficacy of TB medication without inducing drug resistance.

This discovery was made by a team of international scientists led by the Singapore Immunology Network (SIgN), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore.

TB is an air-borne infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb), which often infects the lungs. Even though drugs are available to treat the disease, TB continues to be a major threat to public health, killing close to 1.5 million people every year .

Conventional drugs used to treat TB usually adopt a pathogen-targeted strategy which attacks and kills bacteria directly. This approach has caused Mtb strains to acquire drug resistance, making existing treatments become increasingly ineffective and resulting in a pressing need to design new therapeutic strategies for the disease.

MET as an adjunct treatment for TB

The team of scientists led by SIgN began searching for drugs that could control Mtb replication indirectly. They screened FDA-approved drugs and identified MET, an old anti-diabetic drug that could defend Mtb invasion without targeting the bacteria directly. Instead, MET targets the host cells to trigger the production of a chemical which then damages Mtb and stops its replication. Such indirect, host-targeted approach is less likely to engender drug resistance. The team also discovered that MET improves the efficacy of conventional anti-TB drugs when used in combination with them.

The scientists then validated the findings with patient data provided by the Tuberculosis Clinical Unit at the Tan Tock Seng Hospital, and consequently verified that the use of MET is indeed associated with improved TB control and decreased disease severity. This anti-diabetic drug is therefore a promising adjunctive therapy that could enhance the effectiveness of existing TB treatments. As it is a drug that is currently in use, another benefit of using MET as an adjunct treatment for TB is that it is likely to shorten the time required for clinical trials.

Diabetes drug can boost efficacy of TB medication without causing drug resistance

Study: Low glycemic diet does not improve insulin sensitivity or cardiovascular risk factors

Study: Low glycemic diet does not improve insulin sensitivity or cardiovascular risk factors

FL118 agent shows efficacy as personalized, targeted therapy for certain cancer tumors

A team led by Fengzhi Li, PhD, and Xinjiang Wang, PhD, of Roswell Park Cancer Institute (RPCI) has reported new findings regarding therapeutic targets of the novel anticancer agent FL118. Previous studies from these researchers have showed that FL118 induces cancer cell death, or apoptosis, by inhibiting expression of multiple cell-survival proteins (survivin, Mcl-1, XIAP or cIAP2). Study results published in the peer-reviewed American Association for Cancer Research journal Cancer Research  showed that FL118 can also activate   the p53 tumor-suppressor pathway in cancer cells, encouraging cell senescence,    or aging. In both processes, FL118 demonstrates potent antitumor efficacy,   suggesting additional applications as a personalized, targeted therapy for certain cancer tumors.

In a study of preclinical models of colorectal cancer, the researchers identified an underlying mechanism for the activation of p53 by FL118. The agent activates the p53 tumor-suppressor protein largely independent of ataxia telangiectasia mutated (ATM)-dependent DNA damage-mediated p53 activation. ATM-dependent activation of p53 is usually induced by many — if not all  types of DNA-damage drugs, including camptothecin compounds such as irinotecan and topotecan,  leading  the authors  to  conclude  that  FL118's mechanisms of action are distinct among camptothecin analogues.

"While FL118 is an analogue of irinotecan and topotecan, two FDA-approved cancer drugs that are also based on the naturally occurring compound camptothecin, our findings add further evidence that FL118 has novel mechanisms of action that may make it especially potent against solid tumors and especially effective as a well-tolerated, targeted therapy," said Dr. Li, an Associate Professor of Oncology in the Department of Pharmacology and Therapeutics.

FL118 agent shows efficacy as personalized, targeted therapy for certain cancer tumors

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

In continuation of my update on cisplatin and 5-fluorouracil derivative S-1v

Research suggests that treatment with cisplatin plus S-1 together with thoracic radiotherapy is relatively efficacious and tolerable in patients with locally advanced non-small-cell lung cancer (NSCLC).

Although cisplatin-based chemotherapy with thoracic radiotherapy is a standard treatment for unresectable, locally advanced NSCLC, the outcomes are not satisfactory, explain Katsuyuki Hotta, from Okayama University Hospital in Japan, and colleagues. They investigated the effect of adding the 5-fluorouracil derivative S-1 to the standard treatment in a phase II trial, the primary endpoint of which was the response rate.

A total of 48 patients with stage III NSCLC received cisplatin plus S-1 (at a dose of 40 mg/m2 twice daily from days 1–14 and 29–42 of treatment) with concurrent thoracic irradiation, of whom 37 had a partial response, giving an overall response rate (ORR) of 77%.

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

First-line dacomitinib may improve advanced NSCLC survival

 

Preliminary research suggests that the second-generation tyrosine kinase inhibitor (TKI) dacomitinib (see right structure)may improve progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

Noting that the majority of patients develop resistance to the first-generation TKIs, such as gefitinib and erlotinib (below structures from left and right side respectively), Pasi Jänne (Dana Farber Cancer Institute, Boston, Massachusetts, USA) and co-workers explain that alternative agents are needed to improve patient outcomes.

 

The open-label, phase II trial included 89 treatment-naïve patients with stage IIIB or IV NSCLC who were selected for dacomitinib once-daily treatment on the basis of clinical markers (never or former light smokers) or molecular markers (absence of KRASmutation in non-Asian patients or EGFR mutation).

First-line dacomitinib may improve advanced NSCLC survival

Isis announces top-line results from ISIS-PTP1B Rx Phase 2 study in type 2 diabetes patients

Isis announces top-line results from ISIS-PTP1B Rx Phase 2 study in type 2 diabetes patients

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

In continuation of my update on daclatasvir 

The drug daclatasvir (trade name Daklinza) has been available since August 2014 for the treatment of adults with chronic hepatitis C (CHC) infection. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether this new drug offers an added benefit over the appropriate comparator therapy.

The drug manufacturer presented data for patients without cirrhosis of the liver who are infected with hepatitis C virus (HCV) genotype 1, and for patients with HCV genotype 4. However, these data are unsuitable in various aspects to prove an added benefit.

The manufacturer dossier contained no data at all for three further patient groups with HCV genotype 1 infection (pretreated patients, untreated patients with cirrhosis of the liver, and patients with HIV coinfection) as well as for patients with HCV genotype 3 (with compensated cirrhosis and/or treatment-experienced).

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

Penn researchers find effective way to inhibit inflammatory response during kidney dialysis

Frequent kidney dialysis is essential for the approximately 350,000 end-stage renal disease (ESRD) patients in the United States. But it can also cause systemic inflammation, leading to complications such as cardiovascular disease and anemia, and patients who rely on the therapy have a five-year survival rate of only 35 percent. Such inflammation can be triggered when the complement cascade, part of the body's innate immune system, is inadvertently activated by modern polymer-based dialysis blood filters. New work by Penn researchers has found an effective way to avoid these problems by temporarily suppressing complement during dialysis. Their work appears online in Immunobiology ahead of print.

Over the past several years, lead author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine, Perelman School of Medicine at the University of Pennsylvania, and his colleagues have developed small molecule versions of the drug compstatin, which inhibits a component of the complement immune response called C3. Lambris explains that this next-generation compound, called Cp40, "is a small peptide similar to cyclosporine in many aspects, however it uses a different mechanism of action."

Previous studies by Lambris and his team, in which modern polymer-based hemodialysis filters were perfused with human blood, showed significant complement activation and an increase in inflammatory biomarkers. This response could be suppressed using compstatin, suggesting that it might be used in dialysis to decrease the inflammatory response side effect.

The new study took place in non-human primates to validate Cp40's complement-inhibiting properties in whole animals. Even after undergoing a single session of dialysis using a pediatric hemodialysis filter with high biocompatibility, healthy animals showed strong complement activation with 5 percent of their C3 being converted to a form that can trigger inflammation and stimulate the immune system.

Ref : http://www.upenn.edu/pennnews/news/penn-researchers-tame-inflammatory-response-kidney-dialysis

Penn researchers find effective way to inhibit inflammatory response during kidney dialysis

SLU researcher discovers new information about how antibiotics stop staph infections

In research published in Proceedings of the National Academy of Sciences, assistant professor of biochemistry and molecular biology at Saint Louis University Mee-Ngan F. Yap, Ph.D., discovered new information about how antibiotics like azithromycin stop staph infections, and why staph sometimes becomes resistant to drugs.

Her evidence suggests a universal, evolutionary mechanism by which the bacteria eludes this kind of drug, offering scientists a way to improve the effectiveness of antibiotics to which bacteria have become resistant.

Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

Yap and her research team studied staph that had been treated with the antibiotic azithromycin and learned two things: One, it turns out that the antibiotic isn't as effective as was previously thought. And two, the process that the bacteria use to evade the antibiotic appears to be an evolutionary mechanism that the bacteria developed in order to delay genetic replication when beneficial.

The team studied the way antibiotics work within the ribosome, the site where bacteria translates the genetic codes into protein. When the bacteria encounter a potential problem in copying its genetic material, as posed by an antibiotic, it has a mechanism to thwart antibiotic inhibition by means of "ribosome stalling" that is mediated by special upstream peptide elements.

Ref  http://www.pnas.org/content/111/43/15379.abstract?sid=94feec3e-058d-4239-97fb-bb9db8f148bb

SLU researcher discovers new information about how antibiotics stop staph infections

Mylan announces U.S. launch of Celecoxib Capsules

In continuation of my update celecoxib

Mylan Inc. (Nasdaq: MYL)      announced the U.S. launch of its Celecoxib Capsules,   50 mg,  100 mg,  200 mg, and 400 mg,  one  of the  first  available  generic  versions        of   Pfizer's elebrex®       Capsules,     which    is   indicated for  the  relief  of the  signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and for the management of acute pain in adults.

Celecoxib Capsules, 50 mg, 100 mg, 200 mg, and 400 mg, had U.S. sales of approximately $2.5 billion for the 12 months ending September 30, 2014, according to IMS Health.

Currently, Mylan has 286 ANDAs pending FDA approval representing $111.6 billion in annual brand sales, according to IMS Health. Forty-five of these pending ANDAs are potential first-to-file opportunities, representing $29.5 billion in annual brand sales, for the 12 months ending June 30, 2014, according to IMS Health.

Mylan announces U.S. launch of Celecoxib Capsules

Midazolam drug helps recover full consciousness in traumatic brain injury patient

A patient who had suffered a traumatic brain injury unexpectedly recovered full consciousness after the administration of midazolam, a mild depressant drug of the GABA A agonists family. This resulted in the first recorded case of an "awakening" from a minimally-conscious state (MCS) using this therapy. Although similar awakenings have been reported using other drugs, this dramatic result was unanticipated. It is reported in Restorative Neurology and Neuroscience.

Traumatic brain injuries occur at high rates all over the world, estimated at 150-250 cases per 100,000 population per year. These injuries can result in several outcomes, ranging from vegetative state, minimally conscious state, severe disability to full recovery. In most cases, the outcome will cause catastrophic changes for his/her family and a significant drain on both human and financial resources.

Two years after the injury caused by a motor vehicle accident, the patient was mildly sedated, in order to undergo a CT scan, using midazolam instead of the more commonly used propofol. As the authors described in the article, the patient began to interact with the anesthetist and soon after with his parents. He talked by cellphone with his aunt and congratulated his brother when he was informed of his graduation; he recognized the road leading to his home. When he was asked about his car accident, he did not remember anything and apparently he was not aware of his condition. This clinical status lasted about two hours after drug administration and disappeared quickly thereafter, taking the patient back to the previous condition.

Midazolam drug helps recover full consciousness in traumatic brain injury patient

Scientists zero in on obesity pill 'that could replace the treadmill'

Scientists at Harvard University have created a way of screening potential drugs that turn white fat cells – which are "bad" – into the brown fat cells that are healthier. They have already identified two compounds that work on human cells growing in the laboratory.

Researchers believe it may be possible to lower the levels of white fat, which is linked with diabetes and heart disease, by increasing the proportion of brown fat, which burns off excess energy. It could lead to a “pill that can replace the treadmill” for the control of obesity, they said.

Meanwhile, Imperial College researchers in London have identified an enzyme that drives the craving for sugar in the brain’s hypothalamus, which regulates food intake. The scientists believe the enzyme, called glucokinase, could be a viable target for an anti-obesity drug.

“This is the first time anyone has discovered a system in the brain that responds to a specific nutrient, rather than energy intake in general. It suggests that when you’re thinking about diet, you have to think about different nutrients, not just count calories,” said James Gardiner of Imperial College, who led the study published in the Journal of Clinical Investigation.

Tests on rats showed that boosting the activity of the enzyme within the brain caused the animals to consume more glucose in preference to normal food. A drug targeting glucokinase or its metabolic pathway could potentially prevent obesity by lowering the desire for sugary foods, the scientists suggest.

Scientists zero in on obesity pill 'that could replace the treadmill' - Health News - Health & Families - The Independent

Carboplatin and paclitaxel show promise for advanced thymic carcinoma

In continuation of carboplatin and paclitaxel

A multicentre, phase II study of carboplatin and paclitaxel (CbP) in chemotherapy-naïve patients with advanced thymic carcinoma has shown that the treatment has promising efficacy compared with standard anthracycline-based chemotherapy.

Thymic carcinoma is very rare, and consequently it is hard to investigate it separately from thymoma. Previous studies evaluating chemotherapy regimens have included patients with both types of tumour, explain Takashi Seto (National Kyushu Cancer Center, Fukuoka, Japan) and colleagues.

Forty patients from 21 centres across Japan were enrolled in the current study from May 2008 until November 2010. One patient subsequently dropped out. The sample size was decided on the basis that it was large enough to reject the primary endpoint of an objective response rate (ORR) of 20%.

Carboplatin and paclitaxel show promise for advanced thymic carcinoma

Injectable 3-D vaccines could fight cancer, infectious diseases

One of the reasons cancer is so deadly is that it can evade attack from the body's immune system, which allows tumors to flourish and spread. Scientists can try to induce the immune system, known as immunotherapy, to go into attack mode to fight cancer and to build long lasting immune resistance to cancer cells. Now, researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard's School of Engineering and Applied Sciences (SEAS) show a non-surgical injection of programmable biomaterial that spontaneously assemblesin vivo into a 3D structure could fight and even help prevent cancer and also infectious disease such as HIV. Their findings are reported in Nature Biotechnology.