Pfizer seeks FDA support for its new anti-rheumatoid arthritis pill

In continuation of my update on Tofacitinib

Pfizer seeks FDA support for its new anti-rheumatoid arthritis pill: Pfizer is waiting for the Food and Drug Administration to approve its new pill for rheumatoid arthritis (RA) - the first oral biologic for treating this ailment.

Botanical formula inhibits breast to lung cancer metastasis in mice

Botanical formula inhibits breast to lung cancer metastasis in mice: Scientists at Indiana University Health's Cancer Research Laboratory have found that a sophisticated botanical formula slows human breast cancer growth and inhibits breast to lung metastasis in mice. The formula contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum and Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus and Curcuma longa) and purified nutritional compounds, and showed no toxic side-effects.

Truvada deemed safe & effective in HIV infection risk reduction

Gilead Sciences Inc's Truvada pills are deemed  safe  and  effective  for  reducing the risk of HIV infection, U.S. regulators said on Tuesday. But they recommended a cautious approach for using the drug in efforts to prevent the virus that causes AIDS.

According to the Food and Drug Administration Truvada - a combination of Gilead's HIV drugs Emtriva (also known as emtricitabine see above structure), and Viread (or tenofovir see below left structure), which is already being used by patients with the human immunodeficiency virus, is well (left structure is that of  Tenofovir disoproxil fumarate)   tolerated overall by uninfected people and may prevent infection in high-risk individuals when used in combination with other strategies. The FDA acknowledged a strong correlation between the drug's efficacy at reducing HIV infection and the willingness of those taking it to adhere to the treatment.

Researchers speculated that women may require a higher dose of the drug to prevent infection. They also said the disappointing results may have resulted from women not taking the pills consistently. 

“We know that if the person doesn't take the medication every day they will not be protected,” said Dr. Rodney Wright, director of HIV programs at Montefiore Medical Center in New York and chairman of the AIDS Health Foundation. “So the concern is that there may not be adequate adherence to provide protection in the general population.” (right structure is Emtricitabine).

An outside panel of experts is scheduled to examine the FDA review documents on Thursday and make recommendations that U.S. health regulators will consider in deciding whether the drug should be used as a preventive treatment. Some experts have warned that the drug is only partly effective against HIV and that using it to prevent infection could cause protection from the virus to falter if patients fail to adhere to treatment.

More...

Black pepper compound fights fat

We know the that, black pepper has many medicinal benefits, like  curing illness such as constipation, diarrhea, earache, gangrene, heart disease, hernia, hoarseness, indigestion, insect bites, insomnia, joint pain, liver problems, lung disease, oral abscesses, sunburn, tooth decay, and toothaches. Now Korean researchers report that piperine (see structure below), a pungent compound found in black pepper (Piper nigrum), helps block the formation of new fat cells, a process known as adipogenesis.

"Adipogenesis is a well-organized process regulated by adipogenic transcription factors, such as peroxisome proliferator-activated receptor-gamma (PPAR-gamma), sterol regulatory element binding protein (SREBP) family, and CCAAT-enhancer binding protein (C/EBP) family," the authors write in their introduction. "Of these factors, PPAR-gamma has been focused on its role in adipocyte differentiation. In addition to being induced during adipogenesis, it is both necessary and sufficient for the process."

In addition to other benefits such as enhancing nutrient absorption in the digestive tract, black pepper has been found to reduce blood glucose and lipids. In the current study, Soo-Jong Um, Ji-Cheon Jeong and colleagues tested the effects of black pepper extract and piperine on cultured preadipocytes and found that both inhibited the cells differentiation into mature fat cells. Expression of the genes for PPAR-gamma, SREBP-1c and C/EBP-beta were all found to be decreased, as was the binding of PPAR-gamma to a coactivator known as CREB-binding protein following the administration of either treatment. Piperine was also shown to repress LXR-alpha, another transcriptional factor that is involved in the induction of adipogenesis as well as the synthesis of cholesterol and fatty acids.

"Taken together, our findings suggest that piperine, a major component of black pepper, inhibits fat cell differentiation by down-regulating the transcriptional activity of PPAR-gamma (and LXR-alpha) and suppressing the expression of PPAR-gamma (and LXR-alpha), thus leading to its potential use in the treatment of obesity-related diseases," the authors conclude.

Ref : http://pubs.acs.org/doi/abs/10.1021/jf204514a?prevSearch=%255BContrib%253A%2BSoo-Jong%2BUm%255D&searchHistoryKey=

Grape compound may block the formation of fat cells

Purdue University researchers have come up with the ability of a compound known as piceatannol (see structure)  to help prevent the formation of mature fat cells by blocking the pathways needed for their growth. Piceatannol is an analog of resveratrol, found in grapes and other fruit, which is converted to piceatannol in humans following its consumption.

Purdue assistant professor of food science Kee-Hong Kim and his associates tested piceatannol in cultured preadipocytes, which are immature fat cells. These cells pass through several stages before reaching maturity over a ten day or longer period. "These precursor cells, even though they have not accumulated lipids, have the potential to become fat cells," Dr Kim explained. "We consider that adipogenesis is an important molecular target to delay or prevent fat cell accumulation and, hopefully, body fat mass gain."

Dr Kim's team found that piceatannol bound to the preadipocytes' insulin receptors during their initial stage of fat cell formation, which blocked insulin's ability to control cell cycles and activate genes necessary for the further stages of adipogenesis. "Piceatannol actually alters the timing of gene expressions, gene functions and insulin action during adipogenesis, the process in which early stage fat cells become mature fat cells," Dr Kim stated. "In the presence of piceatannol, you can see delay or complete inhibition of adipogenesis."

"Our study reveals an antiadipogenic function of piceatannol and highlights insulin receptor and its downstream insulin signaling as novel targets for piceatannol in the early phase of adipogenesis," the authors conclude.

Dr Kim hopes to test piceatannol in an animal model as well as find a way to prevent the compound from degrading so that enough is available to the body to prevent fat gain. "We need to work on improving the stability and solubility of piceatannol to create a biological effect," he added.

Ref : http://www.jbc.org/content/287/14/11566.abstract?sid=48fa8a22-7a4d-4561-9585-80d643245a89

Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

 In continuation of my update on antisense drugs...

Isis Pharmaceuticals, Inc.  announced the initiation of a Phase 1 study of ISIS-STAT3Rx, a Generation 2.5 antisense drug designed to treat cancer.  ISIS-STAT3Rx specifically reduces the production of signal transducer and activator of transcription 3 (STAT3). Because STAT3 is over expressed in numerous types of cancers, ISIS-STAT3Rx has the potential to be broadly useful for both solid and liquid tumors.  The ISIS-STAT3Rx development plan is initially focused on key cancers where there is a high unmet medical need and a strong link to STAT3, such as hepatocellular carcinoma (HCC) and ovarian cancer.  Advancements in Isis' technology platform have resulted in the improved potency of Generation 2.5 antisense drugs creating opportunities for drugs like ISIS-STAT3Rx to be effective in the more difficult to treat types of cancer. 

 

"The role of STAT3 as a key factor critical for tumor cell growth and survival of cancer cells has made STAT3 widely viewed as an important target of interest," said David S. Hong, M.D., Assistant Professor, Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center.  "STAT3 is a well understood transcription factor involved in multiple survival mechanisms that intersect with the growth, metastasis and invasiveness of cancer. The ability to selectively inhibit STAT3 could allow us to effectively treat some of the most difficult to treat cancers."

 
Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1691711&highlight=

Two-Drug Therapy Helped Kids With Type 2 Diabetes

Two-Drug Therapy Helped Kids With Type 2 Diabetes:  Children with type 2 diabetes may achieve better blood sugar control with a combination of two drugs, metformin and Avandia, than with metformin alone, a new study suggests. However, Avandia (rosiglitazone) was recently linked...

Scientists Spot How Cox-2 Painkillers Raise Heart Risks

In continuation of my update on COX-II inhibitors....

New research has uncovered how some cox-2 painkillers increase the risk for both heart attacks and stroke. The once popular cox-2 drugs, Vioxx and Bextra, were pulled off the market in 2004 and 2005, respectively, after research showed that both raised the chances of cardiovascular trouble. Meanwhile, Celebrex, a painkiller in the same drug class that remains on the market, carries a "black box" warning alerting patients to potential heart risks.

Now, a team of scientists from the University of Pennsylvania in Philadelphia say that, although cox-2 inhibitors are very good at inhibiting the workings of the cox-2 enzyme -- and thereby easing pain -- they also throw off the cardiovascular system's delicate balance by inhibiting an enzyme that relaxes blood vessels and guards against clotting.

"It's really about a rock and a hard place," said Dr. Christopher Cannon, a cardiologist at Brigham and Women's Hospital in Boston. "There's a balance in the bloodstream of clotting and vasoconstriction, as well as protection against clotting and vasodilation, which means that there's a constant balance of clotting and preventing clotting, and constricting arteries and dilating arteries."

"But with cox-2 inhibitors, they have found that you knock the protective side of that balance off," Cannon said. "And then you're left only with the constrictive part, which means the drugs up the risk for clotting and arterial constriction."

"This problem is bigger than just Vioxx, which no longer exists," he added. "It applies to every single NSAID (non-steroidal anti-inflammatory drug), because with all NSAIDs -- including Celebrex and ibuprofen, which zillions of people take -- the same issue exists. You block out the good stuff and leave the bad stuff unchecked. The one exception is Naproxen, which has an anti-platelet effect that seems to work against stroke and heart attack risk."

"Sometimes you have to take a cox-2 because you have really bad daily pain," said Cannon. "But this is a dose-dependent problem, with the more cox-2 you take the greater the cardiovascular risk. So you have to limit the dose and take the least amount you can get away with, so you can try to control crippling pain but also try not to poison your blood vessels and predispose yourself to clotting and high blood pressure."

Ref : http://stm.sciencemag.org/content/4/132/132ra54.abstract?sid=25c1e6c3-e6ee-449c-ae09-b83f14efc9f2

Avastin not as beneficial to older lung cancer patients | Dana-Farber Ca...

In continuation of my update on Avastin

Beehive Extract Shows Potential as Prostate Cancer Treatment

 Caffeic acid phenethyl ester, or CAPE (see below structure), is a compound isolated from honeybee hive propolis, the resin used by bees to patch up holes in hives. Propolis has been used for centuries as a natural remedy for conditions ranging from sore throats and allergies to burns and cancer. But the compound has not gained acceptance in the clinic due to scientific questions about its effect on cells. 

In a paper published in Cancer Prevention Research, researchers combined traditional cancer research methods with cutting-edge proteomics to find that CAPE arrests early-stage prostate cancer by shutting down the tumor cells' system for detecting sources of nutrition.

"If you feed CAPE to mice daily, their tumors will stop growing. After several weeks, if you stop the treatment, the tumors will begin to grow again at their original pace," said Richard B. Jones, PhD, assistant professor in the Ben May Department for Cancer Research and Institute for Genomics and Systems Biology and senior author of the study. "So it doesn't kill the cancer, but it basically will indefinitely stop prostate cancer proliferation." 

Natural remedies isolated from plant and animal products are often marketed as cure-alls for a variety of maladies, usually based on vague antioxidant and anti-inflammatory claims. While substances such as ginseng or green tea have been occasionally tested in laboratories for their medicinal properties, scientific evidence is commonly lacking on the full biological effects of these over-the-counter compounds.

"It's only recently that people have examined the mechanism by which some of these herbal remedies work," Jones said. "Our knowledge about what these things are actually doing is a bit of a disconnected hodge-podge of tests and labs and conditions. In the end, you're left with a broad, disconnected story about what exactly these things are doing and whether or not they would be useful for treating disease."

To study the purported anti-cancer properties of CAPE, first author Chih-Pin Chuu (now at the National Health Research Institutes in Taiwan) tested the compound on a series of cancer cell lines. Even at the low concentrations expected after oral administration, CAPE successfully slowed the proliferation of cultured cells isolated from human prostate tumors.

CAPE was also effective at slowing the growth of human prostate tumors grafted into mice. Six weeks of treatment with the compound decreased tumor volume growth rate by half, but when CAPE treatment was stopped, tumor growth resumed its prior rate. The results suggested that CAPE stopped cell division rather than killing cancerous cells.

To determine the cellular changes that mediated this effect, the researchers then used an innovative proteomics technique invented by Jones and colleagues called the "micro-western array." Western blots are a common laboratory tool used to measure the changes in protein levels and activity under different conditions. But whereas only one or a few proteins at a time can be monitored with Western blots, micro-western arrays allow researchers to survey hundreds of proteins at once from many samples.

Chuu, Jones and their colleagues ran micro-western arrays to assess the impact of CAPE treatment on the proteins of cellular pathways involved in cell growth -- experiments that would have been prohibitively expensive without the new technique.

"What this allowed us to do is screen about a hundred different proteins across a broad spectrum of signaling pathways that are associated with all sorts of different outcomes. You can pick up all the pathways that are affected and get a global landscape view, and that's never been possible before," Jones said. "It would have taken hundreds of Westerns, hundreds of technicians, and a very large amount of money for antibodies."

The micro-western array results allowed researchers to quickly build a new model of CAPE's cellular effects, significantly expanding on previous work that studied the compound's mechanisms. Treatment with CAPE at the concentrations that arrested cancer cell growth suppressed the activity of proteins in the p70S6 kinase and Akt pathways, which are important sensors of sufficient nutrition that can trigger cell proliferation.

"It appears that CAPE basically stops the ability of prostate cancer cells to sense that there's nutrition available," Jones said. "They stop all of the molecular signatures that would suggest that nutrition exists, and the cells no longer have that proliferative response to nutrition."

The ability of CAPE to freeze cancer cell proliferation could make it a promising co-treatment alongside chemotherapies intended to kill tumor cells. Jones cautioned that clinical trials would be necessary before CAPE could be proven effective and safe for this purpose in humans. But the CAPE experiments offer a precedent to unlock the biological mechanisms of other natural remedies as well, perhaps allowing these compounds to cross over to the clinic.

"A typical problem in bringing some of these herbal remedies into the clinic is that nobody knows how they act, nobody knows the mechanism, and therefore researchers are typically very hesitant to add them to any pharmaceutical treatment strategy," Jones said. "Now we'll actually be able to systematically demonstrate the parts of cell physiology that are affected by these compounds."

Ref : http://cancerpreventionresearch.aacrjournals.org/content/5/5/788

MEDA Announces Dymista Approved by the FDA

MEDA Announces Dymista Approved by the FDA:   The U.S. Food and Drug Administration (FDA) has approved Dymista, a new patented product for treatment of seasonal allergic rhinitis (SAR). In several clinical studies, MP29-02 (tentatively called Dymista), a novel intranasal formulation of azelastine hydrochloride (above left structure)  and fluticasone propionate (right structure).  

The first study demonstrated that continuous treatment with MP29-02 for 1 year was well tolerated in patients with chronic allergic or non-allergic rhinitis, only 2.7% of patients treated with MP29-02 and 2.9% of patients treated with fluticasone propionate discontinued the study due to an adverse event. MP29-02 also provided sustained efficacy over the one-year study period. MP29-02-treated patients experienced consistently greater relief from their nasal symptoms than fluticasone treated patients over the course of the study. Statistically significant (P<.05) differences favoring MP29-02 over fluticasone were observed at months 1 through 7 and at months 9 and 11. 

The second and third studies in patients with seasonal allergic rhinitis (SAR) provided evidence that MP29-02 demonstrated significantly more effective relief of nasal symptoms (P<.05 vs. azelastine, fluticasone, and placebo) and significantly greater ocular benefits compared to placebo (P<.05) over a 2-week study period. The new data was the subject of platform presentations on Sunday, March 4, 2012 at the annual meeting of the American Academy of Allergy Asthma and Immunology (AAAAI) in Orlando, Florida. MP29-02 is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of SAR.

Ref : http://mb.cision.com/Main/357/9255877/10183.pdf

Magnesium supplement helps boost brainpower ....

Neuroscientists at MIT and Tsinghua University in Beijing show that increasing brain magnesium with a new compound enhanced learning abilities, working memory, and short- and long-term memory in rats. The dietary supplement also boosted older rats’ ability to perform a variety of learning tests.

Magnesium, an essential element, is found in dark, leafy vegetables such as spinach and in some fruits. Those who get less than 400 milligrams daily are at risk for allergies, asthma and heart disease, among other conditions. In 2004, Guosong Liu and colleagues at MIT discovered that magnesium might have a positive influence on learning and memory. They followed up by developing a new magnesium compound — magnesium-L-threonate (see structure, MgT) — that is more effective than conventional oral supplements at boosting magnesium in the brain, and tested it on rats.  

“We found that elevation of brain magnesium led to significant enhancement of spatial and associative memory in both young and aged rats,” said Liu, now director of the Center for Learning and Memory at Tsinghua University. “ 

If MgT is shown to be safe and effective in humans, these results may have a significant impact on public health.” Liu is cofounder of Magceutics, a California-based company developing drugs for prevention and treatment of age-dependent memory decline and Alzheimer’s disease.

Magnesium supplement helps boost brainpower - MIT Media Relations

Garlic Oil Component May Form Treatment to Protect Heart

A potent-smelling component of garlic oil may help release protective compounds to the heart after heart attack, during cardiac surgery, or as a treatment for heart failure.

At low concentrations, hydrogen sulfide gas has been found to protect the heart from damage. However, this unstable and volatile compound has been difficult to deliver as therapy.

Now researchers at Emory University School of Medicine have turned to diallyl trisulfide (right structure), a garlic oil component, as a way to deliver the benefits of hydrogen sulfide to the heart. Their findings suggest that doctors could use diallyl trisulfide  in many of the situations where researchers have proposed using hydrogen sulfide.

The data was presented Wednesday, Nov. 16 at the American Heart Association (AHA) Scientific Sessions conference in Orlando.

“We are now performing studies with orally active drugs that release hydrogen sulfide,” says

David Lefer, PhD, professor of surgery at Emory University School of Medicine and director of the Cardiothoracic Surgery Research Laboratory at Emory University Hospital, Midtown. “This could avoid the need to inject sulfide-delivery drugs outside of an emergency situation.”

Garlic Oil Component May Form Treatment to Protect Heart | Emory University | Atlanta, GA

Garlic compound 100 times more effective than antibiotics at fighting food borne illness...

A recent research reveals a potent effect for garlic against the bacteria Campylobacter jejuni, a leading cause of intestinal illness caused by eating undercooked poultry or foods that have been contaminated during poultry preparation. "Campylobacter is simply the most common bacterial cause of food-borne illness in the United States and probably the world," explained coauthor Michael Konkel of Washington State University's College of Veterinary Medicine.

The researchers compared the effects of diallyl sulfide (see structure),  a compound that occurs in garlic, and the antibiotics ciprofloxacin and erythromycin on biofilms formed by Campylobacter jejuni. Biofilms are colonies of bacteria protected by a film that renders them a thousand times more resistant to antibiotics than free cells. Cell death following the administration of diallyl sulfide occurred at a concentration of resveratrol that was 100-fold less than that which was effective for either antibiotic, and often took less time to work. The team found that diallyl sulfide combined with a sulfur-containing enzyme, which altered the cells' function and metabolism.

Researchers conclude that, diallyl sulphide elicits strong antimicrobial activity against planktonic and sessile C. jejuni and may have applications for reducing the prevalence of this microbe in foods, biofilm reduction and, potentially, as an alternative chemotherapeutic agent for multidrug-resistant bacterial strains.

Ref : http://jac.oxfordjournals.org/content/early/2012/04/27/jac.dks138.abstract?sid=71685bd6-4b80-4d25-b97b-9422ba1d8cc3

Combination of Two Drugs Reverses Liver Tumors.....

The combination of two inhibitors of protein mTOR stops the growth of primary liver cancer and destroys tumour cells, according to a study by researchers of the Group of Metabolism and Cancer at Bellvitge Biomedical Research Institute (IDIBELL).  

The study led by IDIBELL researchers compared the effects in mice of two inhibitors of mTOR. The first was a derivative of rapamycin, called everolimus (RAD001 - see structure below left),
which is already used as an immunosuppressant and to treat specific cancers. The second is a new generation drug that inhibits mTOR called BEZ235 (see right side structure). 

During the study, researchers found unexpectedly that the combination of the two drugs had a more potent effect than any of the two drugs separately. Coadministration of BEZ235 and RAD001 limits the development of tumour and causes the self-destruction of tumour cells.

Based on these results a clinical trial, funded by Novartis, has started in the United States to evaluate the efficacy of the combination of these two inhibitors of mTOR in humans. The study coordinator, Sara Kozma, noted that

"because rapamycin and its derivatives are already approved for the treatment of other diseases, their combination to BEZ235, would be a rapid strategy to test the efficacy of this drug and fast track its approval for clinical use."

Ref :1. http://www.idibell.cat/modul/news/en/362/combination-of-two-drugs-reverses-liver-tumours
2.http://stm.sciencemag.org/content/early/2012/04/27/scitranslmed.3003923