Study on current insect repellants confirms need for better insect repellants...

In continuation of update on  mosquito repellents developments and DEET

Now, Johns Hopkins scientists have discovered what it is in the bugs' molecular makeup that enables citronellal (the aromatic liquid used in lotions, sprays and candles) and DEET, to deter insects from landing and feeding on you. A better understanding of these molecular-behavioral links already is aiding the team's search for more effective repellants.

Researchers claim that, three taste receptors on the insects' tongue and elsewhere are needed to detect DEET. Citronellal detection is enabled by pore-like proteins known as TRP (pronounced "trip") channels. When these molecular receptors are activated by exposure to DEET or citronellal, they send chemical messages to the insect brain, resulting in an aversion response.

"DEET has low potency and is not as long-lasting as desired, so finding the molecules in insects that detect repellents opens the door to identifying more effective repellents for combating insect-borne disease," says Craig Montell, Ph.D., a professor of biological chemistry and member of Johns Hopkins' Center for Sensory Biology.

As per the lead researcher, when a mosquito lands, it tastes your skin with its gustatory receptors, before it bites. Researchers suggests that,  one of the reasons DEET is relatively effective is that it causes avoidance responses not only through the sense of smell but also through the sense of taste.

The team filled feeding plates with high and low concentrations of color-coded sugar water (red and blue dyes added to the sugar), allowing the flies to feed at will and taking note of what they ate by the color of their stomachs: red, blue or purple (a combination of red and blue). Wild-type (normal) flies preferred the more sugary water to the less sugary water in the absence of DEET. When various concentrations of DEET were mixed in with the more sugary water, the flies preferred the less sugary water, almost always avoiding the DEET-laced sugar water.Flies that were genetically engineered to have abnormalities in three different taste receptors showed no aversion to the DEET-infused sugar water, indicating the receptors were necessary to detect DEET. 

"We found that the insects were exquisitely sensitive to even tiny concentrations of DEET through the sense of taste," Montell reports. "Levels of DEET as low as five hundredths of a percent reduced feeding behavior."

To add to the evidence that three taste receptors (Gr66a, Gr33a and Gr32a) are required for DEET detection, the team attached recording electrodes to tiny taste hairs (sensilla) on the fly tongue and measured the taste-induced spikes of electrical activity resulting from nerve cells responding to DEET. Consistent with the feeding studies, DEET-induced activity was profoundly reduced in flies with abnormal or mutated versions of Gr66a, Gr33a, and Gr32a. 

In the second study, Montell and colleagues focused on the repellent citronellal. To measure repulsion to the vapors it emits, they applied the botanical compound to the inside bottom of one of the two connected test tubes, and introduced about 100 flies into the tubes. After a while, the team counted the flies in the two tubes. As expected, the flies avoided citronellal. 

The researchers identified two distinct types of cell surface channels that are required in olfactory neurons for avoiding citronellal vapor. The channels let calcium and other small, charged molecules into cells in response to citronellal. One type of channel, called Or83b, was known to be required for avoiding DEET. The second type is a TRP channel. 

The team tested flies with mutated versions of 11 different insect TRP channels. The responses of 10 were indistinguishable from wild-type flies. However, the repellent reaction to citronellal was reduced greatly in flies lacking TRPA1. Loss of either Or83b or TRPA1 resulted in avoidance of citronellal vapor.

The team then "mosquito-ized" the fruit flies by putting into them the gene that makes the mosquito TRP channel (TRPA1) and found that the mosquito TRPA1 substituted for the fly TRPA1. Researchers found that the mosquito-version of TRPA1 was directly activated by citronellal. Montell's lab and others have tallied 28 TRP channels in mammals and 13 in flies, broadening understanding about how animals detect a broad range of sensory stimuli, including smells and tastes.

Hop this discovery now raises the possibility of using TRP channels to find better insect repellents.

Ref 1: http://www.cell.com/current-biology/abstract/S0960-9822%2810%2901006-7
      2 : http://download.cell.com/neuron/pdf/PIIS0896627310005441.pdf?intermediate=true

Naringenin (grape fruits) initiates increased fatty acid oxidation, inhibits vLDL production...

Naringenin is a flavonoid that is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, anti-inflammatory, carbohydrate metabolism promoter, and immune system modulator. It is the predominant flavanone in grapefruit. It  has been shown to have an inhibitory effect on the human cytochrome P450 isoform CYP1A2, which can change pharmacokinetics in a human (or orthologous) host of several popular drugs in an adverse manner, even resulting in carcinogens of otherwise harmless substances. Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes (liver cells) in cell culture. This seem to be secondary to Naringenin ability to inhibit the secretion of very-low-density lipoprotein by the cells.It has been reported that Naringenin,  lowers the plasma and hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet. 

Now interestingly, researchers from Hebrew University of Jerusalem and Massachusetts General Hospital (MGH) report that naringenin activates a family of small proteins, called nuclear receptors, causing the liver to break down fatty acids. In fact, the compound seems to mimic the actions of other drugs, such as the lipid-lowering Fenofibrate and the anti-diabetic Rosiglitazone, offering the advantages of both. If the results of this study extend to human patients, this dietary supplement could become a staple in the treatment of hyperlipidemia, type-2 diabetes, and perhaps metabolic syndrome.

The researchers demonstrated that the compound activates PPARα and PPARγ by dramatically increasing the levels of a co-activator peptide of both, called PGC1α. At the same time, naringenin bound directly to LXRα, blocking its activation. These effects culminated with increased fatty acid oxidation and the inhibition of vLDL ('bad cholesterol') production.  

"It is a fascinating find," says Yaakov Nahmias, PhD, of the Hebrew University of Jerusalem the paper's senior author. "We show the mechanism by which naringenin increases two important pharmaceutical targets, PPARα and PPARγ, while blocking a third, LXRα. The results are similar to those induced by long periods of fasting".

Authors claim that, it is a process which is similar to the Atkins diet, without many of the side effects and the liver behaves as if fasting, breaking down fatty acids instead of carbohydrates. 

"Dual PPARα and PPARγ agonists, like naringenin, were long sought after by the pharmaceutical industry," says Nahmias, "but their development was plagued by safety concerns. Remarkably, naringenin is a dietary supplement with a clear safety record. Evidence suggests it might actually protect the liver from damage."....

 Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012399

Plantain and broccoli fiber help in Crohn’s disease........

In continuation of my update on dietary benefits of broccoli....

New research from University School of Clinical Sciences in Liverpool, lead by Prof. Jonathan Rhodes,  suggests that plant fibers in plantains and broccoli can help prevent relapses of Crohn's disease. This disease is a long term disease of the gut that is characterized by inflammation of the lining of the digestive system, with symptoms including diarrhea and abdominal pain. Scientists believe that rise in processed food and decrease in fibers in diet could be a reason for rise of incidence of this disease.

For this study the scientists tested a range of soluble plant fiber to judge their effect on Crohn's disease. Soluble plant fiber is the kind which comes out of vegetables when they are boiled in water. The results of the study showed that soluble fiber from plantain and broccoli specifically stopped 45% to 82% of the bacteria E.coli from crossing into cells in the intestine. Fiber from leek and apple had no effect.

The sticky E. coli are capable of penetrating the gut wall via special cells, called M-cells that act as 'gatekeepers' to the lymphatic system. Studies have shown that patients with Crohn's disease this leak leads to chronic inflammation in the gut. This study shed that plantain soluble fibers prevented the uptake and transport of E. coli across M.cells. They compared these results with tests on polysorbate-80 - a fat emulsifier used in processed food to bind ingredients together. The tests revealed that polysorbate had the opposite effect to plantain fibers, and encouraged the movement of bacteria through the cells.

The research shows that different dietary components can have powerful effects on the movement of bacteria through the bowel. We  know  the general health benefits of eating plantain and broccoli, which are both high in vitamins and minerals, but until now we have not understood how they can boost the body's natural defences against infection common in Crohn's patients. This work, suggests that it might be important for patients with this condition to eat healthily and limit their intake of processed foods.

Ref : http://www.liv.ac.uk/researchintelligence/issue23/ibd.html

Experimental drug PLX4032 holds promise against cancers with faulty BRAF gene....

Plexxikon  recently announced the publication of data from the Phase 1 clinical trial of PLX4032 (RG7204), confirming that treatment of metastatic melanoma patients with the BRAF ^V600E (mutation resulted in significant tumor shrinkage in the majority of patients). The company claims that, in the melanoma extension cohort of the study, nearly all patients showed some response; 81 percent of patients had tumor shrinkage of at least 30 percent and the company concludes that these results further support the current PLX4032 development strategy, which includes parallel and ongoing Phase 2 (BRIM2) and Phase 3 (BRIM3) studies to support registration. PLX4032 is a novel, orally administered, targeted agent that is selective for a key oncogenic driver in melanoma and other cancers. 

Primary objectives of the melanoma extension cohort were to establish further safety and pharmacokinetics (PK) data beyond the dose-escalation phase, as well as demonstrate proof-of-concept in the target patient population at the MTD of 960 mg twice daily.

Results Demonstrate Significant Anti-tumor Activity with PLX4032 . In the melanoma extension cohort, in which 32 patients with metastatic melanoma harboring the BRAF mutation were enrolled, data showed an 81 percent response rate by RECIST criteria, including:  2 complete responses (no evidence of disease) and 24 partial responses (tumor shrinkage of at least 30 percent)

As per the claim by the company, all patients except two showed some tumor regression. The estimated median progression-free survival (PFS) among these patients was at least seven months as of January 31, 2010, compared to historical PFS of less than two months. Sixteen patients were still on study as of January 31, 2010.

Company also claims that, drug-related adverse events were predominantly mild in severity and included rash, joint pain, photosensitivity and fatigue. Among the 48 patients treated in the dose-escalation and extension cohorts, 18 patients developed cutaneous squamous cell carcinoma in sun exposed areas of the skin (primarily keratoacanthoma subtype) that were treated by excision, while treatment with PLX4032 was continued.

This PLX4032 trial represents the first evidence that a treatment that targets activating BRAF mutations can induce significant tumor regressions in patients," said Dr. K. Peter Hirth, CEO  of  Plexxikon. He adds that "these data are particularly encouraging, with responses observed at all sites of disease, including challenging visceral lesions in the bone, liver and small bowel and  they are  hopeful that PLX4032 will provide similar benefit to these patients so urgently in need of effective therapies."..

PLX4032 is currently being tested in a randomized, controlled Phase 3 (BRIM3) trial in previously untreated metastatic melanoma patients who test positive for the BRAF mutation. Enrollment for the trial is currently under way. The primary endpoint for the BRIM3 trial is overall survival....

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1002011

Spoonful of black rice bran contains more health promoting anthocyanin antioxidants than blueberries

Spoonful of black rice bran contains more health promoting anthocyanin antioxidants than blueberries

FDA approves Chelsea Therapeutics' Phase II protocol for CH-4051 antifolate in rheumatoid arthritis

Chelsea Therapeutics International, Ltd. announced the  confirmation by the U.S. FDA,  that its proposed Phase II protocol for CH-4051  in rheumatoid arthritis has been approved by the agency. Chelsea plans to initiate patient screening next month and initiating treatment in October.

This multi-national, double-blind, randomized Phase II trial of CH-4051, an orally available metabolically stable antifolate, is intended to evaluate the safety and efficacy of CH-4051 in a 250-patient head-to-head study against methotrexate (MTX). Patients with rheumatoid arthritis who are experiencing an inadequate response to MTX treatment will be randomized to receive daily oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 3.0 mg plus folate of CH-4051 or 20 mg weekly dose of MTX plus folate supplement for 12 weeks following a two-week MTX-washout. The primary efficacy analysis will be conducted using the hybrid American College of Rheumatology, or ACR, score (hACR), which allows for a more comprehensive assessment of treatment benefit across all seven symptomatic and functional components of the standard ACR 20/50/70 evaluations historically used in RA trials.

"Although MTX is considered the standard of care in RA, both as a monotherapy and in combination with other RA treatments, the dosing and maximal therapeutic benefit of MTX is limited by well-documented tolerability issues, long-term safety concerns and variable bioavailability," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "Given that CH-4051 is metabolically stable and that all of our preclinical and clinical work suggests enhanced absorption, dramatically increased potency and improved tolerability over MTX, we believe CH-4051 will be safe and highly efficacious in a historically treatment-resistant patient population."

Chelsea intends to conduct an un-blinded interim efficacy analysis after approximately 50% of patients in the two lower CH-4051 dose groups complete treatment and expect to report results from this analysis in the third quarter of 2011. Full study results, inclusive of all dose groups, are expected in mid-2012.

As previously reported, results from Chelsea's Phase I single and multiple ascending dose studies demonstrated that CH-4051 was well tolerated at doses up to and including 7.5mg, a dose range likely to be effective for multiple autoimmune disorders. The 5mg dose was as well tolerated as placebo. No serious adverse events occurred during the study and pharmacokinetic data indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in the study were comparable to those seen in animal pharmacology studies in which CH-4051 demonstrated superior suppression of RA than both the maximally tolerated dose of methotrexate and equivalent doses of CH-1504 (see structure)....

Ref : http://www.irconnect.com/chtp/pages/news_releases.html?d=200159

New compound may be effective against Chagas' disease

New compound may be effective against Chagas' disease

Ref : http://www.asm.org/images/Communications/chagas%20-%20aac.pdf

Researchers Identify Two FDA Approved Drugs (Decitabine and Gemcitabine) That May Fight HIV....

Researchers at the University of Minnesota Academic Health Center have identified two drugs (Decitabine and Gemcitabine see structures)  that when combined, may serve as an effective treatment for HIV.

The researchers found that, two drugs, decitabine (left) and gemcitabine (below) (both FDA approved and currently used in pre-cancer and cancer therapy) were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death an outcome researchers dubbed "lethal mutagenesis." Interestingly, this is for the first time that, this novel approach has been used to attack the deadly virus without causing toxic side effects. As the drugs are already approved for other purpose, it will be much easier to expedite the development of the drugs for human use.

"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.

HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite evolve beyond control, to the point of extinction.

The lead researcher claims that HIV's ability to mutate makes it difficult to target and treat, and they wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself.

Researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.

Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV. And now the researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.

Ref : http://jvi.asm.org/cgi/content/abstract/84/18/9301

Endothelial Function Improvement With Dietary (Cocoa) Flavanols in Patients With Coronary Artery Disease....

A new study by UCSF cardiologists and researchers lead by Dr. Yerem Yeghiazarians found that high concentrations of cocoa flavanols decrease blood pressure, improve the health of blood vessels and increase the number of circulating blood-vessel-forming cells in patients with heart disease. The findings indicate that foods rich in flavanols  such as cocoa products, tea, wine, and various fruits and vegetables have a cardio-protective benefit for heart disease patients.

Flavanols are phytonutrient compounds that are found naturally in apples, grapes, tea, cocoa and cherries, which account for the antioxidant effect provided by red wine and green tea. The study found a protective effect from a cocoa drink with 375 mg of flavanols, but according to researchers, a standard or recommended dosage has not yet been defined to achieve optimal health benefit.

The UCSF team has shown for the first time that one of the possible mechanisms of flavanol's benefit is an increase in the circulation of so-called angiogenic cells in the blood. These cells, also known as early endothelial progenitor cells, are critical for the repair process after vascular injury, and perform function and maintenance roles in the endothelium. Endothelium is the thin layer of cells that line the interior wall of blood vessels.

In the current study, the benefit seen from the two-fold increase in circulating angiogenic cells was similar to that achieved by therapy with statins and with lifestyle changes such as exercise and smoking cessation. The benefit demonstrated with cocoa flavanol therapy occurred in addition to the medical regimen already being taken by study participants.

"Our data support the concept that dietary flavanols at the levels provided -- in tandem with current medical therapy -- are safe, improve cardiovascular function, and increase circulating angiogenic cells, which have previously been shown to correlate positively with long-term cardiovascular outcomes" said Yeghiazarians.

Though long-term trials examining the effects of high-flavanol diets on cardiovascular health and function are warranted, but these early findings help us understand how these compounds impact the function of damaged blood vessels...

Ref : Yerem Yeghiazarians et.al., J. Am. Coll. Cardiol., July 13, 2010; 56: A20. 

New Anti-Viral Drug Shows Promise for Dramatic Improvement in Hepatitis C Treatment

Research team, led by Paul Kwo, M.D., of Indiana University School of Medicine, reported that adding the drug boceprevir, nearly doubled the treatment's effectiveness when given for 48 weeks in one treatment arm of the study. We knew that, Boceprevir (see structure) is a protease inhibitor being studied as a treatment for hepatitis C. It was being developed by Schering-Plough and has since been absorbed into the Merck's new pipeline since its acquired Schering in 2009. As of 2008, it is in phase II clinical trials (SPRINT-1 trial). Researchers claim that, adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients.

Researchers claim that, the drug boceprevir increased the cure rate to as high as 75 percent in those who received 48 weeks of the three-drug combination therapy, compared to 38 percent of those in the control group, who received the standard two-drug treatment (peginterferon alfa-2b plus ribavirin)   for 48 weeks, said Dr. Kwo, associate professor of medicine at the IU School of Medicine. The two-year phase 2 trial was conducted at 67 sites with 520 patients in the US, Canada and Europe.

In the boceprevir study, known as the SPRINT-1 trial, researchers tested several different options to evaluate the effectiveness of the combination therapy.

"Both 28- and 48-week boceprevir regimens significantly increased sustained virologic response rates  which is the best definition of a cure we have  compared to the 48 week control," said Dr. Kwo. "The 48-week treatment arm with 4 weeks of peg interferon lead-in and 44 weeks of peg interferon, ribavirin, and boceprevir led to the largest improvement over the control group ever reported. That's very impressive." 

Researchers conclude that, best results were reported for the 103 patients who were treated for four weeks with the standard two drug regiment, followed by 44 weeks of the three-drug regimen including boceprevir: 75 percent of these patients tested negative for evidence of the virus six months after the end of treatment.

As per the lead researcher, Dr. Kwo, based on this phase 2 study, it appears that if this drug receives final approval approximately two-thirds of patients will be able to be treated successfully with 28 weeks of treatment and one-third will need 48 weeks of treatment, though this will require confirmation from the phase 3 trials, from which preliminary results were recently released.

Ref  : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960934-8/fulltext

Etoricoxib better than tramadol for postoperative pain.....

In continuation of my update on Etoricoxib...

Researchers lead by Dr. Metha Brattwall of University Hospital Möndal in Gothenburg, Sweden, have come up with an  interesting finding, i.e., for patients with moderate pain after foot surgery, the cyclo-oxygenase 2 (COX-2) inhibitor drug etoricoxib provides better pain relief with fewer side effects than the opioid drug tramadol. The study also helps to alleviate concerns that COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with bone healing after surgery.  The researchers compared two different pain-relieving drugs in 100 women undergoing surgery for bunions (hallux valgus). One group received the COX-2 inhibitor etoricoxib, while the other group received tramadol, an opioid (narcotic-like) drug similar to codeine.

Although both drugs were effective in controlling pain in the week after surgery, pain scores were significantly lower in the etoricoxib group. Women assigned to etoricoxib had an average pain score of 12.5 (on a 100-point scale), compared to 17 in those receiving tramadol.  As per the claim by  the researchers, patients in the etoricoxib group had lower maximum pain scores throughout the week after surgery. They also had better pain relief on the second and third days after surgery, when pain scores were highest.

"Etoricoxib was also associated with fewer side effects and thus overall patient satisfaction with pain medication," the researchers write...

Interesting results from this study are that, no evidence of impaired healing in patients taking NSAIDs, at least after a relatively minor operation like bunion surgery. Etoricoxib is not currently approved for use in the United States, but is available in other countries. NSAIDs are generally considered much safer than opioid drugs.And this research further substantiate this.

"The results suggest that NSAIDs can provide superior analgesia for patients with moderate pain after bone surgery, with reduced risk," Dr. Shafer adds...

Ref : Metha Brattwall,  Ibrahim Turan, and Jan Jakobsson, Anesthesia & Analgesia

ProstaCaid (33-ingredient comprehensive polyherbal preparation) against prostate cancer......

We have seen  many benefits of natural products rich in  Quercetin,   Epigallocatechin gallate (EGCG) and many other polyphenol antioxidant from natural products like green tea, broccoli peaches and plums. Interestingly, now researchers from  Columbia University have come up with an interesting finding, i.e., ProstaCaid is a 33-ingredient comprehensive polyherbal preparation with supplements of vitamin C, vitamin D3, zinc, selenium, quercitin, 3,3′-diinodolymethane (DIM), and lycopene was able to stop abnormal cell growth and induce apoptosis (programmed cell death) in both hormone sensitive and hormone resistant prostate cancer cell lines at unusually low concentrations, which makes the findings more significant...

Herbal extracts include the extracts from turmeric root, saw palmetto berry, grape skin, pomegranate, pumpkin seed, pygeum bark, sarsaparilla root, green tea, and Japanese knotweed. Hence, it is rich in natural polyphenols, including quercetin, resveratrol, epigallocatechin gallate (EGCG), and ellagic acid, which have previously demonstrated anticancer potential. The unique formula contains 3 medicinal mushrooms grown on an herbal-enhanced medium. The mushrooms included are Phellinus linteus, Ganoderma lucidum, and Coriolus versicolor, each with known anticancer properties.

Researchers claim that, ProstaCaid was designed based on constituents that exhibit antiprolifetaive, antioxidant, and apoptotic activities; however, its efficacy and the mechanisms of action are yet to be examined. Researchers looked at the effectiveness of the preparation in suppressing several types of prostate cancer cell lines in culture and attempt to delineate the mechanism of action for justification in pursuing animal to determine efficicacy invivo.

Researchers conclude that, the anticancer activity of ProstaCaid may be ascribed to its polyphenolic flavonoids and curcuminoids derived from various herbs as well as other supplements, such as DIM. The preparation contains supplements such as quercetin (15%), Curcuma longa root extract complex with enhanced bioavailability (BCM-95; 20%), DIM (3%), and resveratrol (0.2%). Some of these components have shown a strong doseand time-dependent growth inhibition and apoptotic death in prostate cancer cells; 25 mM of quercetin inhibited about 50% PC3 cell growth for 72 hours. At 24 hours, 50 mM and 100 mM quercetin induced G2/M arrest and apoptosis, manifested by the decrease in G2/M-related protiens.

Researchers summarise  that,    ProstaCaid has anti-cancer activities in both AD and AI prostate cancer cells at very low concentrations (25 mg/mL). It also suggests that ProstaCaid inhibits cell growth and survival, at least through the inhibition of AKT and MAPK signaling. The effect on AI cell lines is especially of importance as there is presently no curative therapy for hormone refractory prostate cancer.

Researchers postulate that ProstaCaid may affect activity of Cdc2/cyclin B1 kinase by reducing this complex formation. Cdc2 could be dephosphorylated by Cdc25C and become inactive or be phosphorylated by protein kinase, such as Wee1, and then converted into an inactive form. They also suggest that more studies are needed in the future to test it and to define its upstream events in PC3 cells.

Ref : Jun Yan and Aaron E. Katz, Integr Cancer Ther 2010 9: 186

Carfilzomib could become new option for patients with relapsed myeloma, IMF says

 In continuation of my update on Carfilzomib
 

The International Myeloma Foundation (IMF), the oldest and largest foundation dedicated to improving the life and care of myeloma patients, today said promising data suggest that the new drug "carfilzomib" could become an important new option for patients whose myeloma stops responding to other therapies. Carfilzomib, from Onyx Pharmaceuticals, is a next-generation proteasome inhibitor that disrupts the life cycle of a cancer cell, and carfilzomib has shown favorable tolerability. Based on this Phase II clinical trial, Onyx could seek accelerated drug approval from the FDA by the end of 2010.

More....

Ref : http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=3082&aTab=-1

Impressive Results of Velcade(R) (bortezomib) Based Therapy in Multiple Myeloma...

 In continuation of my update on Bortezomib [1, 2]

The Takeda Oncology Company today reported new correlative science data from the pivotal PINNACLE trial of VELCADE^® (bortezomib) in patients with relapsed/refractory mantle cell lymphoma (MCL). The data, derived from an analysis of archived tumor samples, tested pre-specified biomarkers for their association with time to progression and response to treatment with VELCADE in patients with relapsed MCL. The results add to the body of data supporting the potential usefulness of biomarkers in predicting outcome of MCL and predicting responsiveness to single agent VELCADE.

"This analysis of the PINNACLE study opens the door for additional research into targeted approaches to VELCADE treatment."..

The PINNACLE trial was a Phase II, open-label, single-arm, multicenter study of 155 patients with relapsed/refractory MCL and was the basis of the 2006 approval of VELCADE for the treatment of patients with relapsed/refractory MCL who had received one prior therapy. The overall response rate in the trial was 31 percent, with a median duration of response of 9.3 months; the CR rate was 8 percent, with a median duration of response of 15.4 months.

The Goy analysis used archived tumor samples from 73 patients who participated in the PINNACLE trial. The biopsies were examined for biomarkers associated with poor prognosis in MCL or those regulated by the proteasome. The biomarker levels were then compared to the effect of VELCADE on patients, according to response rates including overall survival and time to progression...

Ref : http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1434934&highlight=

New Class of Drugs for Treating Epileptic Seizures....

A chemical compound called Galanin,  that boosts the action of a molecule normally produced in the brain may provide the starting point for a new line of therapies for the treatment of epileptic seizures, according to a new study by scientists at "The Scripps Researcher Institute".

"This compound really provides a new angle for developing drugs to treat seizures," says Scripps Research Assistant Professor Xiaoying Lu..

Galanin is a peptide, a fragment of a protein, produced in the brain to regulate a variety of functions, such as pain, memory, addition, mood, and appetite. In the late 1990s, researchers discovered that galanin is also a potent anticonvulsant.

Recent research suggests that when seizures occur the brain steps up production of galanin, possibly as a way to protect itself against the seizures. As a result, mice engineered to lack galanin are more susceptible to developing seizures.

Because galanin seems to play a role in reducing seizures, several groups of researchers, including those at Scripps Research, have been working to develop drugs that target the galanin system. The first category of such compounds consists of synthetic molecules that mimic galanin's functions (called agonists) and include Galnon, developed by Bartfai's group. Galnon and other galanin agonists have been shown to act as anticonvulsants when given to animals that were rendered prone to developing seizures. But these agonists have several drawbacks as potential therapeutic agents. For one thing, because Galnon acts relativly broadly, it may have unwanted side effects.

Interestingly, now Lu, Roberts, Bartfai, and colleagues at Scripps Research have now designed a compound that targets the galanin system but, unlike the previous agonists, is more selective in its action. The compound, dubbed CYM2503, binds to one of the three receptors for galanin on nerve cells, the galanin receptor type 2 (GalR2). On its own, CYM2503 has no effect on GalR2, but when galanin also binds to the receptor, CYM2503 boosts galanin's function.

The researchers tested the effects of CYM2503 on mice and rats that had received a chemical causing them to have seizures. The animals that received CYM2503 took longer to get the seizures and, when they did, the seizures lasted for a shorter time. Most importantly, when the researchers looked at the animals after 24 hours, the rats that had been treated with CYM2503 had a dramatically higher survival rate than those that had not.

This mechanism of action, modifying a receptor's function, is common to many successful drugs that have been developed for the treatment of a number of conditions, including epilepsy, hyperparathyroidism, and AIDS, but not yet for drug candidates targeting galanin system.

Because CYM2503 only works when galanin, a natural molecule, is also present, the researchers predict it will have fewer side effects than drugs that work on their own. This study provides the first evidence that modulating the GalR2 receptor is an effective strategy for treating seizures, thus opening the door for the development of drugs that target this mechanism.

"It is a double breakthrough" . "The compound is a first new mode-of-action anticonvulsant and it represents a new mechanism of molecular action." Also based on the known functions of the GalR2 receptors, it may also work in treating depression and in protecting the brain from damage," says Lu...

Ref : http://www.scripps.edu/news/press/20100728.html