Friday, November 30, 2012

Diabetes drug rosiglitazone, improves memory, study suggests

In continuation of my update on rosiglitazone 

Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule.

"Using this drug appears to restore the neuronal signaling required for proper cognitive function," said UTMB professor Larry Denner, the lead author of a paper describing this work now online in the Journal of Neuroscience. "It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer's patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer's."

Ref : http://www.utmb.edu/newsroom/article8071.aspx

Tuesday, November 27, 2012

New drug, regorafenib overcomes resistance in patients with rare sarcoma, study suggests

In continuation of my update on regorafenib

A new targeted drug demonstrated its ability to control metastatic gastrointestinal stromal tumor, an uncommon and life-threatening form of sarcoma, after the disease had become resistant to all existing therapies, report investigators at Dana-Farber Cancer Institute who led the worldwide clinical trial.

The oral drug regorafenib (see structure), which inhibits several cancer-promoting kinase enzymes, was able to control GIST for nearly four months longer than placebo in patients for whom Gleevec and Sutent were no longer effective, a result that was highly significant statistically.

"When added to best supportive care, regorafenib significantly improves disease control, as measured by progression-free survival time in patients with GIST after progression which represents failure of all other therapies," said George Demetri, MD, of Dana-Farber, principal investigator of this clinical trial.
Demonstrating the aggressive nature of this resistant disease, the study found that tumors objectively grew in less than a month, on average, in GIST patients who were initially randomized to receive a placebo. The study's "cross-over" design made it possible to treat those patients whose tumors grew, and 85 percent of the patients initially on placebo were able to receive regorafenib, which then controlled the disease in these patients as well.

Because of the study's cross-over design, Demetri said, it was not expected to prove that the patients initially randomized to receive regorafenib survived longer -- the researchers would have had to withhold the drug from the placebo patients to demonstrate that difference. "But there is no question that people are living longer" with regorafenib treatment, he said, based on the results of this trial.
An application to have regorafenib approved for use in resistant GIST is under an accelerated review by the Food and Drug Administration, Demetri said.

Sunday, November 25, 2012

Positive results from Genentech Avastin plus temozolomide Phase III study on glioblastoma

Positive results from Genentech Avastin plus temozolomide Phase III study on glioblastoma: Genentech, a member of the Roche Group, today announced results from the positive Phase III AVAglio study. The study showed Avastin (bevacizumab) in combination with radiation and temozolomide (see structure below) chemotherapy reduced the risk of cancer worsening or death (progression-free survival; PFS) by 36 percent compared to radiation and temozolomide chemotherapy plus placebo>17th Annual Meeting of the Society for Neuro-Oncology in Washington, D.C.

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=14247

Saturday, November 24, 2012

CLR01 effectively inhibits synaptotoxicity in mice with Alzheimer's



We know that, aggregation of α-synuclein (α-syn) is implicated as being causative in the pathogenesis of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Despite several therapies that improve symptoms in these disorders, none slow disease progression. Recently, a novel“molecular tweezer”(MT) termed CLR01 (see structure) has been described as a potent inhibitor of assembly and toxicity of multiple amyloidogenic proteins....


"This is the first demonstration that molecular tweezers work in a mammalian animal model," said Gal Bitan, an associate professor of neurology at UCLA and the senior author of the study. "Importantly, no signs of toxicity were observed in the treated mice. The efficacy and toxicity results support the mechanism of this molecular tweezer and suggest these are promising compounds for developing disease-modifying therapies for Alzheimer's disease, Parkinson's and other disorders."

Molecular tweezers are complex molecular compounds capable of binding to other proteins. Shaped like the letter "C," these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins. Bitan and his colleagues, including Aida Attar, first author of the study and a graduate student in Bitan's lab, have been working with a particular molecular tweezer called CLR01.
In collaboration with scientists at the Università Cattolica in Rome, the researchers, working first in cell cultures, found that CLR01 effectively inhibited a process known as synaptotoxicity, in which clumps of toxic amyloid damage or destroy a neuron's synapses.
Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities.


Friday, November 23, 2012

Natural product produced by marine algae shows promise in stroke recovery treatment


A new study using brevetoxin-2 (see structure), a compound produced naturally by marine algae, stimulated nerve cell growth and plasticity in cultured mouse neurons. This research advances a potentially new pharmacological treatment to aid recovery of brain function following a stroke or other traumatic brain injury.

"Our research suggests that compounds like brevetoxin-2 can augment neuronal plasticity potentially providing a neural repair therapy for stroke recovery. If that outcome can be supported by further studies in animals and subsequently humans, it could have a profound impact on a currently non-treatable condition," said Thomas F. Murray, Ph.D. associate vice president for Health Science Research and professor and chair of the Department of Pharmacology, Creighton School of Medicine.


The tiny marine dinoflagellate Karenia brevis produces brevetoxin, which in high concentrations is responsible for the harmful algal blooms known as red tides that occur in the waters off the west coast of Florida. The neurotoxin-laden red tide causes respiratory irritation in humans and central nervous system paralysis in fish.

"Brevetoxin is a neurotoxin that is known to activate nerves cells to fire spontaneously," said Dan Baden, Ph.D. He is director of the Center for Marine Science as well as a founding member and Executive Principal of MARBIONC at University of North Carolina Wilmington. "It's a great advancement to show that this naturally occurring ocean compound can stimulate nerve cell growth in cultured mouse cells."

Brevetoxin is one of more than 1,000 ocean organisms cultured at the University of North Carolina Wilmington's MARBIONC facility (Marine Biotechnology in North Carolina) for use in bio-medical research. The bioactive materials from Karenia brevis have been actively studied by Baden since the early 1970s. A clot that restricts blood flow to an area of the brain causes a stroke. Although the dead tissue cannot be revived, the brain can be trained to redirect nerve impulses to living nerve cells nearby.

Ref : http://www.pnas.org/content/early/2012/11/09/1212584109


Thursday, November 22, 2012

Drug shrinks brain tumors in children with tuberous sclerosis complex, study suggests

In continuation of my update on Everolimus

 "Every patient in this study experienced a decrease in size of their tumors, and no patient required surgery for their tumors after treatment with everolimus," says Dr. Franz, co-director of the TSC Clinic at Cincinnati Children's and the study's main author. "Thirty-five percent of patients in this study on everolimus had at least a 50 percent reduction in tumor volume after an average of 42 weeks on medication."

The phase III study was conducted among 117 patients with TSC who were randomly assigned to either everolimus or a placebo. Patients were 9 ½ years old on average but ranged from infants to adults. No patient on placebo showed improvement in their tumors. Tumor volume was measured by MRI assessment of the brain.

Dr. Franz conducted an earlier, phase II study of everolimus published in The New England Journal of Medicine in 2010. Based on that data, the U.S. Food and Drug Administration granted accelerated approval of everolimus for patients with these tumors, known as subependymal giant cell astrocytomas, or SEGAs. The new, placebo controlled study was conducted to confirm these earlier results.

Prior to FDA approval, surgery was considered standard therapy for SEGAs, but everolimus is a potential alternative to surgery and the first targeted medical therapy for TSC, says Dr. Franz.

"Children and teens may not only avoid surgery but they also may see improvement in other aspects of this disease, including a reduction or even elimination of hydrocephalus  a buildup of fluid inside the skull leading to increased intracranial pressure. Hydrocephalus is commonly associated with these tumors because they are located deep within the brain in spinal fluid pathways, or ventricles."

In Dr. Franz's 2010 study, patients reported their quality of life, as measured by a validated quality of life and neuropsychological assessments, improved at three months and six months after treatment with everolimus...

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61134-9/fulltext


Wednesday, November 21, 2012

Smart drug improves survival in older patients with acute myeloid leukemia


Gemtuzumab ozogamicin (marketed by Wyeth as Mylotarg) is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010. It was withdrawn from market in June 2010 when a clinical trial showed the drug increased patient death and added no benefit over conventional cancer therapies.

Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins. CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells. In the United States, it was approved under an accelerated-approval process by the FDA in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.

Within the first year after approval, the FDA required a black box warning be added to Gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation. Later the onset of VOD was shown to occur at increased frequency in Gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents. 

Common side effects of administration included shivering, fever, nausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory system, tumor lysis syndrome, Type III hypersensitivity, venous occlusion, and death. 

Now researchers from a major phase III Cancer Research UK-funded trial led by Cardiff University, have come out with an interesting conclusion that is, adding GO to treatment could improve the effectiveness of chemotherapy without excessively increasing side effects, providing a potential lifeline for older AML patients who are often too frail to tolerate more intensive chemotherapy regimes.....


Tuesday, November 20, 2012

Drug trio of rapamycin, sildenafil and doxorubicin improved effectiveness of cancer treatment, protected heart


Combining cancer medication with a drug for erectile dysfunction and one for heart transplants helped kill cancer cells and protected the heart from damage. For decades, doxorubicin has been a powerful anti-cancer treatment for various human cancers, including breast, ovarian, colon and prostate. But its use has been limited due to harmful, possibly irreversible effects on the heart.

In this study, using cell and animal models, researchers found that sildenafil alone or in combination with rapamycin (an immunosuppressant used to prevent post-transplant organ rejection) significantly improved the anti-cancer effects of doxorubicin while protecting the heart. The combination of all three medications showed the most powerful effect, researchers said.

"Because sildenafil and rapamycin are clinically approved drugs that both protect heart muscle, we thought that combining these drugs with doxorubicin would be a unique strategy to eliminate the cardiac side effects of doxorubicin while further improving its cancer-killing ability," said Rakesh Kukreja, Ph.D., study co-author and professor of internal medicine and cardiology, Virginia Commonwealth University (VCU) School of Medicine in Richmond.

"The drug combination led to a dramatic protection of heart muscle from apoptosis (cellular self-destruction) and, to a lesser extent, necrosis (cell death from disease)," said David E. Durrant, study lead author and Ph.D. candidate at the VCU School of Medicine. "We think this combination therapy may have excellent potential to move forward into clinical trials and eventually improve life expectancy of cancer patients."



Monday, November 19, 2012

Breast cancer drug, geldanamycin could halt other tumors

The drug, geldanamycin, is well known for attacking a protein associated with the spread of breast cancer. However, a laboratory-based study found it also degraded a different protein that triggers blood vessel growth.

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0048539