Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

In continuation of my update on Nilotinib

The anticancer drug nilotinib induces clearance of the toxic protein alpha-synuclein from   neurons in a mouse model of Parkinson's disease and ameliorates symptoms of the disease.

Investigators at Georgetown University Medical Center (Washington DC, USA) worked with a mouse model of Parkinson’s disease. They reported in the May 10, 2013, online edition of the journal Human Molecular Genetics that lentiviral transfection of the gene encoding alpha-synuclein into the mouse SN lead to activation (phosphorylation) of the tyrosine kinase Abl and that lentiviral transfection of the gene encoding Abl increased alpha-synuclein levels, which exacerbated the disease. Administration of the tyrosine-kinase inhibitor nilotinib decreased Abl activity and increased autophagic clearance of alpha-synuclein into lysosomes in transgenic and lentiviral gene-transfer models.

The drug nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In 2006, a Phase I clinical trial found that nilotinib had a relatively favorable safety profile and showed activity in cases of CML resistant to treatment with imatinib (Gleevec [USA]/ Glivec [Europe, Australia, and Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study, 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment.

In the current study, nilotinib, which enters the brain within [US] Food and Drug Administration approved doses, led to autophagic degradation of alpha-synuclein, protection of SN neurons and improvement of motor performance in the Parkinson’s disease mice.

 
"No one has tried anything like this before," said senior author Dr. Charbel E-H Moussa, assistant professor of neuroscience at the Georgetown University Medical Center. "This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain."

"The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death," said Dr. Moussa. "We reasoned that small doses—for these mice, an equivalent to 1% of the dose used in humans—would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else. We successfully tested this for several diseases models that have an accumulation of intracellular protein. It gets rid of alpha-synuclein and tau in a number of movement disorders, such as Parkinson's disease as well as Lewy body dementia."

Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

New Hepatitis C Drug Sovaldi Approved by FDA

A new hepatitis C drug that can be taken as a pill once a day was approved by the U.S. Food and Drug Administration on Friday.

The drug, called Sovaldi and made by Calif.-based Gilead Sciences Inc., works faster and should be much simpler to take for the millions of Americans who have the virus, which can destroy the liver if left untreated.

The FDA said in a statement that Sovaldi is to be taken with older drugs to treat the main forms of hepatitis C. The agency added that 3.2 million Americans have the disease, and people born between 1945 and 1965 are five times more likely to be infected.

Current treatments can take almost a year to beat back the virus, and involve weekly injections of the drug interferon, which can cause diarrhea and flu-like symptoms, the FDA said. Only about 75 percent of patients are cured with current treatments. In clinical trials, Sovaldi cured close to 90 percent of patients in just 12 weeks, when combined with the standard treatment.

Sovaldi (sofosbuvir) is the second hepatitis C drug to be approved by the FDA in the past two weeks. In November, the agency gave its blessing to Olysio (simeprevir), made by Janssen Pharmaceuticals, of Raritan, N.J.

Symptoms of hepatitis C disease may not appear until two or three decades after infection, though the virus can cause liver failure, cirrhosis and cancer, the FDA said.

New Hepatitis C Drug Sovaldi Approved by FDA - Drugs.com MedNews

Experimental Drug Pritelivir Shows Promise for Genital Herpes Treatment

An experimental drug could eventually offer a new treatment option for genital herpes, a common and incurable sexually transmitted infection, researchers report.

In a small study, researchers found that the drug -- called pritelivir -- substantially curbed "viral shedding" in people with genital herpes. That means it decreased the amount of time the virus was active and potentially transmissible to patients' sexual partners.

The findings, reported in the Jan. 16 issue of the New England Journal of Medicine, are based on 156 patients followed for just four weeks. Experts cautioned that the study is preliminary and offers a "proof of concept."

Still, they said, the results are important because pritelivir is the first in a new class of drugs that works differently than existing medications for genital herpes. The hope is that pritelivir will be better at preventing transmission of the virus.

"There was a fairly dramatic decrease in the probability of viral shedding in this study," said Dr. Richard Whitley, an infectious disease expert at the University of Alabama at Birmingham.

There is still a lot of research to be done, said Whitley, who wrote an editorial published with the study. But he said it's good news that drugs that work in new ways are under development.

"We're at the beginning of a new era" in genital herpes treatment, Whitley said.

Experimental Drug Pritelivir Shows Promise for Genital Herpes Treatment

Potential drug targets for early onset glaucoma

Using a novel high-throughput screening process, scientists have for the first time identified molecules with the potential to block the accumulation of a toxic eye protein that can lead to early onset of glaucoma.

Glaucoma is a group of diseases that can damage the eye's optic nerve and cause vision loss and blindness. Elevated eye pressure is the main risk factor for optic nerve damage.

Researchers have implicated a mutant form of a protein called myocilin as a possible root cause of this increased eye pressure. Mutant myocilin is toxic to the cells in the part of the eye that regulates pressure. These genetically inherited mutants of myocilin clump together in the front of the eye, preventing fluid flow out of the eye, which then raises eye pressure. This cascade of events can lead to early onset-glaucoma, which affects several million people from childhood to age 35.

To find molecules that bind to mutant myocilin and block its aggregation, researchers designed a simple, high-throughput assay and then screened a library of compounds. They identified two molecules with potential for future drug development to treat early onset glaucoma.

"These are really the first potential drug targets for glaucoma," said Raquel Lieberman, an associate professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, whose lab led the research.

Lieberman presented her findings on January 20 at the Society for Laboratory Automation and Screening conference in San Diego, Calif.

The study was published on Nov. 26, 2013, in the journal ACS Chemical Biology. The National Institutes of Health and the Pew Scholar in Biomedical Sciences program provided support for the research. The work was a collaboration involving Georgia Tech, Emory University and the University of South Florida.

Ref : 1. http://pubs.acs.org/doi/abs/10.1021/cb4007776

         2. http://www.sciencedirect.com/science/article/pii/S0022283613007407

Potential drug targets for early onset glaucoma  

New drug shows promise in treating indolent non-Hodgkin lymphomas

Slow-growing, or indolent, non-Hodgkin lymphomas are difficult to treat, with most patients relapsing repeatedly and the disease becoming increasingly resistant to therapy over time.

But a new drug made by Seattle-based Gilead Sciences Inc. appears to offer hope for fighting the disease, according to a study published online today in The New England Journal of Medicine in advance of its March 13 print issue.

The phase 2 study involved 125 patients aged 33 to 87 with indolent non-Hodgkin lymphoma (iNHL) who had not responded to conventional treatments or had relapsed within six months of therapy. The patients, who were from the Seattle area, around the United States and Europe, were given a twice-daily dose of idelalisib, a highly selective oral drug that inhibits phosphoinositide 3-kinase (PI3K) delta. P13K deltas are a family of enzymes seen in many types of B-cell malignancies.

Following treatment with idelalisib, tumor size shrunk by at least half in 57 percent of the patients and 6 percent had no measurable evidence of cancer.

"These are patients who had exhausted current standard therapies," said Ajay Gopal, M.D., a member of Fred Hutchinson Cancer Research Center's Clinical Research Division and the study's lead and corresponding author. "In terms of effective therapy available, there really wasn't much left."

Indolent non-Hodgkin lymphomas comprise about one-third of all cases of NHL. About 20,000 people in the United States were diagnosed with iNHL in 2012 and approximately 7,000 died of the disease. The standard treatment for iNHL is a combination of rituximab, a drug that targets the protein CD20 found on B cells, and chemotherapy.

New drug shows promise in treating indolent non-Hodgkin lymphomas -- ScienceDaily

Scientists develop powerful new animal model for metastatic prostate cancer

Prostate cancer is the most common form of cancer in men. Affecting about 1 in 6 men, it is the second deadliest cancer. Research has been stymied by imperfect animal models of the disease, which are costly, take considerable time to develop, and fail to mimic the most lethal aspects of the illness. Now, Cold Spring Harbor Laboratory (CSHL) scientists have developed a new method to rapidly create much better mouse models for metastatic prostate cancer. This discovery allows scientists to investigate the causes of the disease while at the same time testing new therapeutics to treat it.

More at 

Ref: http://cancerdiscovery.aacrjournals.org/content/early/2014/01/24/2159-8290.CD-13-0346

Scientists develop powerful new animal model for metastatic prostate cancer  

Birch helps wounds heals faster.....

Extracts from the birch tree have served for centuries as a traditional means of helping the damaged skin around wounds to regenerate more quickly. Prof. Dr. Irmgard Merfort from the Institute of Pharmaceutical Sciences of the University of Freiburg and her team have now explained the molecular mechanism behind the wound-healing effect of an extract from the outer white layer of the tree's bark. The scientists published their findings in the journal Plos One. The team cooperated with several other departments and institutes, such as a research group from the Institute of Molecular Medicine and Cell Research and the Institute of Experimental and Clinical Pharmacology of the University of Freiburg as well as a research group from the Dermatological Clinic of the University of Hamburg.

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0086147

Birch helps wounds heals faster -- ScienceDaily

US Indian scientist ‘re-engineering’ tulsi "to control breast cancer"

US Indian scientist ‘re-engineering’ tulsi -  to  control breast cancer"

Led by an Indian-American, a team of scientists at a US university are genetically engineering tulsi or basil to enhance its pharmaceutical value, the institute said.

In his lab at the Owensboro facility, Chandrakanth Emani, Assistant Professor of Plant Molecular Biology at the Western Kentucky University and his students are genetically engineering the basil to produce more eugenol, a compound in basil that “has a very great pharmaceutical value because it's shown to  control breast cancer,” the University said in a statement.

“When you grind these basil leaves there is a compound called eugenol that comes out...Eugenol, when they put it on a plate where there are tumor cells, it stopped growth of the tumour cells. That was a proof of concept experiment which was done a long time back,” Prof Emani claimed.

“If I make it make higher and higher amounts of eugenol, that plant, basil plant, will be a storehouse of that anti-cancerous compound,” he said.

The next phase would be to test the compound as an effective cancer treatment. Prof Emani is also working to understand various basic cell functions.

Biology News

New Drug Combo Might Help Older, Sicker Patients With Leukemia

The research, led by German scientists, included nearly 800 older people (average age 73) who had been diagnosed with chronic lymphocytic leukemia. CLL is a cancer of the blood and bone marrow, the tissue inside bones in which blood cells are created.

The study was published online Jan. 8 in the New England Journal of Medicine. Study participants -- none of whom had received treatment for their illness before the start of the research -- were randomly assigned to one of three groups.

One group received an oral medication called chlorambucil (also known by the brand name Leukeran), the standard chemotherapy drug for older patients with CLL.

The second group received chlorambucil plus a drug called rituximab (Rituxan). This drug has been used effectively in combination with other forms of chemotherapy for more than a decade to treat younger, fitter patients with CLL, an expert said.

The third group received chlorambucil plus a new antibody drug called obinutuzumab. The rituximab and obinutuzumab were given intravenously.

The researchers, whose study was funded by the manufacturer of both obinutuzumab and rituximab, reported that the obinutuzumab-chlorambucil combination improved outcomes for the older CLL patients better than the other two treatment options.

The most common side effects for obinutuzumab are infusion reactions, low blood cell counts, fever, cough and musculoskeletal disorders, according to the manufacturer's website.

Dr. William Wierda, a professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, said older patients don't tend to tolerate intensive chemotherapy with rituximab as well as younger patients. That has left older CLL patients with limited drug options, including chlorambucil, he said.

"We've been wanting to find a treatment that is effective and well tolerated in the elderly population," said Wierda, who was not involved with the new research. "A standard treatment for older patients with CLL has been chlorambucil, a type of chemotherapy that's been used for many years."

"The trial shows improvement in outcome remission rates and duration favoring patients who got chlorambucil and obinutuzumab," he said. "This was a head-to-head comparison of the two antibody arms of the study -- the rituximab and the obinutuzumab -- and obinutuzumab won out."

There also was an improvement in overall survival among the patients who received the obinutuzumab-chlorambucil combination treatment versus those who received chlorambucil alone, Wierda said.

New Drug Combo Might Help Older, Sicker Patients With Leukemia - Drugs.com MedNews

New Drug Combo Might Help Older, Sicker Patients With Leukemia - Drugs.com MedNews

Mekinist Plus Tafinlar Approved for Late-Stage Melanoma

The U.S. Food and Drug Administration on Friday approved Mekinist for use with another drug, Tafinlar, to treat advanced melanoma that is spreading or cannot be removed by surgery.

Melanoma is the most deadly form of skin cancer, accounting for an estimated 9,480 American deaths last year, the FDA said Friday in a news release. Mekinist (trametinib) is newly approved to be used in combination with Tafinlar (dabrafenib). Both drugs were first sanctioned in May 2013 to be used by themselves to battle advanced melanoma, the agency said.

The combination therapy is newly approved for people who have certain mutations in the BRAF V600E and V600K genes, the FDA said. About half of melanoma cases have the mutated genes.

The combination therapy was clinically evaluated in 162 people. Of those treated, 78 percent had their cancer shrink or disappear for an average of 10.5 months, the agency said.

Mekinist Plus Tafinlar Approved for Late-Stage Melanoma - Drugs.com MedNews

FDA Approves Anoro Ellipta to Treat COPD

A new inhaled drug to treat a serious lung condition called chronic obstructive pulmonary disease (COPD) has been approved by the U.S. Food and Drug Administration.

GlaxoSmithKline's Anoro Ellipta [Combination of umeclidinium bromide -(see structure-1 left) and vilanterol-structure-2 rightside below) is meant to be used once a day for long-term maintenance of airflow in patients with COPD. The lung disease makes breathing difficult and worsens over time.   

"Anoro Ellipta works by helping the muscles around the airways of the lungs stay relaxed to increase airflow in patients with COPD," Dr. Curtis Rosebraugh, director of the Office of Drug Evaluation II in the FDA's Center for Drug Evaluation and Research, said in an agency news release.

"The availability of new long-term maintenance medications provides additional treatment options for the millions of Americans who suffer with COPD," he added.

FDA Approves Anoro Ellipta to Treat COPD - Drugs.com MedNews

Farxiga Approved for Type 2 Diabetes - Drugs.com MedNews

In continuation of my update on Farxiga

Farxiga (dapagliflozin) has been approved by the U.S. Food and Drug Administration to treat adults with type 2 diabetes, the agency said Wednesday in a news release.

The drug, to be used for blood sugar control along with proper diet and exercise, is designed to prevent re-absorption of glucose by the kidneys. Type 2 diabetes affects some 24 million people, accounting for 90 percent of diabetes cases in the United States, the FDA said.

Farxiga Approved for Type 2 Diabetes - Drugs.com MedNews

Chinese herbal compound relieves inflammatory, neuropathic pain

Working with Chinese scientists, Olivier Civelli and his UC Irvine colleagues isolated a compound called dehydrocorybulbine (DHCB) from the roots of the Corydalis yanhusuo plant. In tests on rodents, DHCB proved to diminish both inflammatory pain, which is associated with tissue damage and the infiltration of immune cells, and injury-induced neuropathic pain, which is caused by damage to the nervous system. This is important because there are no current adequate treatments for neuropathic pain.

Moreover, the researchers found that DHCB did not generate the tolerance seen with continued use of most conventional pain relievers, such as morphine.

"Today the pharmaceutical industry struggles to find new drugs. Yet for centuries people have used herbal remedies to address myriad health conditions, including pain. Our objective was to identify compounds in these herbal remedies that may help us discover new ways to treat health problems," said Civelli, the Eric L. & Lila D. Nelson Chair in Neuropharmacology. "We're excited that this one shows promise as an effective pharmaceutical. It also shows a different way to understand the pain mechanism."

Study results appear in the Jan. 20 issue of Current Biology.

They are the product of a collaboration between two teams separated by the Pacific Ocean. As traditional Chinese medicine gains greater acceptance in Western medical practice, Xinmiao Liang at the Dalian Institute of Chemical Physics in China and his group have been working to create an "herbalome" of all the compounds in plant extracts that display pharmacological properties. The UC Irvine team suggested applying "reverse pharmacology"   a novel drug discovery approach that Civelli devised about 25 years ago   to the herbalome project.

Together they screened 10 traditional Chinese medicines known as analgesics, testing nearly 500 compounds for their pain-relief abilities. Only DHCB in corydalis induced a reproducible effect.

Corydalis is a flowering herbal plant that grows in Siberia, Northern China and Japan. People utilize its root extract to alleviate menstrual cramps, chest pain and abdominal pain. It's been previously studied for its analgesic properties, but this is the first time DHCB has been identified, extracted and tested.

Chronic neuropathic pain affects more than 50 million Americans, yet management of this pain remains a major clinical challenge due to the poor results and severe side effects of conventional analgesics. Civelli said that drawing upon traditional Chinese medical-herbal products could lead to a breakthrough treatment for these patients.

Chinese herbal compound relieves inflammatory, neuropathic pain

2 Pre-Surgery Drug Treatments Show Promise Against Aggressive Breast Cancer - Drugs.com MedNews

This pre-surgical drug therapy boosts the likelihood that no cancer cells will be found in breast tissue removed during either mastectomy or lumpectomy, according to two new studies.

The approach, called "neoadjuvant" chemotherapy, is being given to an increasing number of women with what's known as triple-negative breast cancer. Currently, the approach results in no identifiable cancer cells at mastectomy or lumpectomy in about-one third of patients, experts estimate. In such cases, the risk of a tumor recurrence becomes lower.

"Chemotherapy [before surgery] does work in triple-negative breast cancer. What we want to do is make it work better," said study researcher Dr. Hope Rugo.

Rugo is director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

Triple-negative cancers have cells that lack receptors for the hormones estrogen and progesterone. In addition, they don't have an excess of the protein known as HER2 on the cell surfaces. So, treatments that work on the receptors and drugs that target HER2 don't work in these cancers.

In two new studies, researchers got better results by adding drugs to the standard chemo regimen prior to surgery. However, both studies are phase 2 trials, so more research is needed.

Both studies are due to be presented Friday at the annual San Antonio Breast Cancer Symposium.

Rugo compared standard neoadjuvant therapy -- paclitaxel (Taxol, others), doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan, others) -- to standard therapy plus the drugs veliparib (investigational) and carboplatin (Paraplatin)....

2 Pre-Surgery Drug Treatments Show Promise Against Aggressive Breast Cancer - Drugs.com MedNews

Two-drug combo helps adolescents with ADHD, aggression

Prescribing both a stimulant and an antipsychotic drug to children with physical aggression and attention-deficit/hyperactivity disorder (ADHD), along with teaching parents to use behavior management techniques, reduces aggressive and serious behavioral problems in the children, according to a study conducted by researchers at The Ohio State University Wexner Medical Center….

For the "Treatment of Severe Childhood Aggression (TOSCA) Study," 168 children ages 6 to 12 who had been diagnosed with ADHD and displayed significant physical aggression were divided into two groups. All study participants received a psychostimulant drug called OROS methylphenidate (left structure) and their parents received behavioral parent training for nine weeks. The researchers called this treatment combination "basic" because both are evidence-based and have been shown to be helpful for improving both ADHD and aggression.

Researchers wanted to see if they could expand or augment this treatment by adding a second medication. If there was room for improvement at the end of the third week, a placebo was added for the "basic group," while the antipsychotic drug risperidone (right above structure)  was added for participants in the "augmented group."

Compared to the "basic group," the "augmented group" who received the stimulant drug and parent training plus risperidone showed significant improvement (on average with moderately better behavior) on the Nisonger Child Behavior Rating Form (NCBRF) Disruptive-Total Scale, the NCBRF Social Competence subscale and the Reactive Aggression part of the Antisocial Behavior Scale.

While there is always some risk with the addition of a second drug to the treatment package, the two drugs seemed to neutralize some of each other's potential side effects. For instance, children in the augmented group did not seem to have as much trouble falling asleep, once the risperidone was added, Aman said.

"We conducted this study because we viewed the combination of ADHD and significant physical aggression -- especially the aggression -- as a serious situation," Aman said. "It is not uncommon to use more than one medicine for other serious situations, such as when treating cancer or epilepsy for instance. Although doctors have often used stimulants and antipsychotics together in recent years, we did not have good evidence until now that they would work more effectively when carefully staged and given together."

Ref : http://dx.doi.org/10.1016/j.jaac.2013.09.022

Two-drug combo helps adolescents with ADHD, aggression