Happy New Year 2010

Wishing one and all a happy, prosperous and peaceful new year 2010...

Dr.Umesh




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Combination of Phentermine & Topiramate for obesity treatment......

We know that Phentermine (see structure) is  an appetite suppressant of the  amphetamine and phenethylamine class. It is approved as an appetite suppressant to help reduce weight in obese patients. Its  usually used for short-term and in combination with exercise, diet and behavioral modification. Is typically prescribed for individuals, who are at increased medical risk because of their weight and works by helping to release certain chemicals in the brain that control appetite.  

Mode of action : Phentermine, in doses clinically used, works on the hypothalamus portion of the brain to release norepinephrine, a neurotransmitter or chemical messenger that signals a fight-or-flight response, reducing hunger. Phentermine works outside the brain as well to release epinephrine or adrenaline causing fat cells to break down stored fat, but the principal basis of efficacy is hunger-reduction. At high doses, phentermine releases serotonin and dopamine as well, but such doses are never used in clinical medicine.  

Topiramate (structure below), is a known anticonvulsant agent and  also  reported  for  the  treatment   of

SSRI-  induced weight gain in anxiety disorders. However a combination   of these two drugs (Phentermine & Topiramate) has been  tried by VIVUS, Inc. and has submitted New Drug Application (NDA)   to the U.S. Food and Drug Administration (FDA) seeking approval of Qnexa (Phentermine & Topiramate combination) - its investigational drug for the treatment of obesity, including weight loss and maintenance of weight loss, in patients who are obese or overweight with co-morbidities such as hypertension, type 2 diabetes, dyslipidemia or central adiposity.

The NDA submission follows the successful completion of the phase 3 program for Qnexa, including the recently announced results from the two pivotal, year-long phase 3 studies (EQUIP and CONQUER). In these trials, patients treated with all three doses of Qnexa achieved significant percent and categorical weight loss compared to placebo and met regulatory requirements for weight loss products as defined in the current FDA Guidance for Developing Products for Weight Management. Patients treated with Qnexa also had significant dose-related improvements in a variety of secondary endpoints including reductions in cardiovascular and metabolic risk factors. Hope people with obesity, will breathe a sigh of relief in the near future....

Ref : http://ir.vivus.com/releasedetail.cfm?ReleaseID=433172

Gren tea for new type of H1N1 Flu ......

In continuatation of my update on Epigallocatechin gallate (EGCg), I find this info something different and interesting too. We are aware about the antioxidant and anticancer activities of this compound, but now researchers from Central Research Institute of ITO EN, Ltd., & School of Pharmaceutical Sciences, University of Shizuoka have found the same compound to inhibits flu infection. As per the researchers claim, the compound had an inhibitory effect against three types of influenza viruses, including the swine-origin H1N1 virus that caused pandemic flu in 2009, and that its effect did not depend on the type of virus. These findings once again suggest that green tea is effective in preventing flu.

Gargling with green tea has already proved to prevent the onset of seasonal flu. It has become clear that catechin, a major type of polyphenol in green tea, plays a major role in prevention of flu infection, and that, among different types of catechin, EGCg displays the strongest antiviral activity. More interestingly, the researchers have conducted examinations to see if EGCg also shows antiviral activity against the new type of H1N1 virus, regardless of viral subtypes.

Solutions containing three types of viruses including the H1N1 virus were mixed with EGCg extracted from green tea. The mixture was added to cultured cells, which were thus infected. The cells were incubated for a set period of time, and the number of infected cells was counted. The concentration of EGCg at which virus infection was inhibited to 50% of the level of infection without EGCg was calculated.

The experiments showed that EGCg prevented flu virus infections at lower concentrations than Amantadine (a drug used to prevent and treat flu). A typical concentration of EGCg in green tea infused from a teapot is reported as 5,000-7,000 micromoles/L. Therefore, these results indicate that green tea diluted 1,000-fold or more is effective to halve infections by three types of viruses, including H1N1.

Those interested to know the details about green tea can visit the site.

Ref : http://www.itoen.co.jp/eng/corporate_info/index.html

Bromo furanones a new class of antimicrobials.....

We know that Candida albicans is the most virulent  Candida species of medical importance, which presents a great threat to immunocompromised individuals such as HIV patients. Candida albicans is carried by about 75 percent of the public. Typically the fungus is harmless but, in individuals with HIV or otherwise compromised immune systems, it can cause candidiasis, which has a high mortality rate. The fungi can also form biofilms that attach to surfaces and are up to 1,000 times more resistant to anti-fungals.

Currently, there are only four classes of antifungal agents available for treating fungal infections: azoles (Diflucan, flucanazole), polyenes, pyrimidines, and echinocandins. The fast spread of multidrug resistant C. albicans strains has increased the demand for new antifungal drugs.

Now two Syracuse University scientists have developed new brominated furanones (see structure) that exhibit powerful anti-fungal properties.

As per the claim by the researchers, the compound exhibited more than 80 percent. Structure and activity of this class of furanones reveals that the exocyclic vinyl bromide conjugated with the carbonyl group is the most important structural element for fungal inhibition. Furthermore, gene expression analysis using DNA microarrays showed that 3 μg/mL of 4-bromo-5Z-(bromomethylene)-3-butylfuran-2-one (BF1) upregulated 32 C. albicans genes with functions of stress response, NADPH dehydrogenation, and small-molecule transport, and repressed 21 genes involved mainly in cell-wall maintenance.

Interestingly, only a small overlap is observed between the gene expression changes caused by the representative brominated furanone in this study and other antifungal drugs reported in literature. This result suggests that brominated furanones and other antifungal drugs may target different fungal proteins or genes.

The existence of such new targets provides an opportunity for developing new agents to control fungal pathogens which are resistant to currently available drugs.

The research team has also shown previously that these furanones inhibit bacterial biofilm formation; thus they may help control chronic infections where biofilms often appear, on surgical, dental and other implants. Hope broad spectrum of other potential capabilities make this class of compounds a new way to combat the microbes in the days to come...

Ref : http://springerlink.com/content/92735526v5013088/

Mitaplatin as a better anticancer agent.......

In continuation of my update on Platinum compounds as anticancer drugs, I find  this one more interesting info to share with. MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

As per the claim by the researchers, glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. With this idea behind researchers have prepared the new compound by combining dichloroacetate, DCA and cisplatin. Mitaplatin, thus obtained has two DCA units which are appended to the axial positions of a six-coordinate Pt (IV) center.

As per the claim by the authors, the negative intracellular redox potential reduces the platinum to release cisplatin, a Pt (II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt (IV) compounds and is comparable to that of cisplatin.

Mitaplatin alters the mitochondrial membrane potential gradient of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance. Further studies like mice transplanted with human tissues are to be substantiated, in my opinion its a good achievement...

Ref : http://www.pnas.org/content/early/2009/12/09/0912276106.abstract?related-urls=yes&legid=pnas;0912276106v1

Mode of action of Cordycepin (a drug from cordyceps mushroom) established.....

We know that Cordycepin, or 3'-deoxyadenosine (known polyadenylation inhibitor),   was initially extracted from fungi of genus Cordyceps, (Cordyceps is a strange parasitic mushroom that grows on caterpillars). 3'-Deoxy adnosine has shown to possess diverse activities such as anti-proliferative, pro-apoptotic and anti-inflammatory effects. Properties attributed to cordyceps mushroom in Chinese medicine made it interesting to investigate and it has been studied for some time. In fact, the first scientific publication on cordycepin was in 1950 . Now it can be prepared from a cultivated form and also by synthetically. The problem was that although cordycepin was a promising drug, it was quickly degraded in the body. Now researcher Dr. de Moor has come up with interesting explanation about how the drug works.

The team has observed two effects on the cells: at a low dose cordycepin inhibits the uncontrolled growth and division of the cells and at high doses it stops cells from sticking together, which also inhibits growth. Both of these effects probably have the same underlying mechanism, which is that cordycepin interferes with how cells make proteins. At low doses cordycepin interferes with the production of mRNA, the molecule that gives instructions on how to assemble a protein. And at higher doses it has a direct impact on the making of proteins. More interestingly, the team has developed a very effective method that can be used to test new, more efficient or more stable versions of the drug in the Petri dish...

Ref : http://www.bbsrc.ac.uk/media/releases/2009/091223-new-insights-mushroom-derived-drug-for-cancer.html

Trabectedin for advanced soft tissue sarcoma....

Patients with a rare form of cancer called advanced soft tissue sarcoma could now benefit from a new drug called trabectedin, after the National Institute for Health and Clinical Excellence (NICE) approved the drug for NHS use.The same drug was given orphan status for ovarian cancer & soft tissue sarcoma by USFDA. Hope patients suffering from soft tissue sarcoma will breathe a sigh of relief.

Research suggests that the drug may extend life by at least three months more than other NHS treatments and that it may therefore be beneficial for some of the 500 to 600 people in England and Wales with advanced soft tissue sarcoma.

Under the latest guidance, the drug is recommended as a treatment for people with advanced soft tissue sarcoma who have previously failed to respond to treatment with anthracyclines and ifosfamide, or who are unable to tolerate those treatments. More...

Pyramidine core- a new drug for drug resistant non small cell lung cancers

Dana-Farber investigators hypothesized current agents lose their potency because they don't bind as tightly or fully to the EGFR T790M protein as they ideally should. To improve the fit, researchers led by chemical biologist Nathanael Gray, PhD, prepared a group of inhibitors with a different structural scaffold, known as a pyrimidine core, which, it was thought, would mesh more thoroughly. They lab-tested the agents in NSCLC cells with EGFR T90M and found several that were up to 100 times more potent than quinazolines [erlotinib (Tarceva), gefitinib (Iressa), and cetuximab (Erbitux)] in restricting cell growth. As an unexpected bonus, these compounds were nearly 100 times less powerful at slowing the growth of cells with normal EGFR, suggesting they would be less likely to produce side effects than current drugs. The agent which performed the best is the pyrimidine WZ4002. Those interested, can watch the video description (Pasi Jänne).

http://www.dana-farber.org/abo/news/press/2009/research-yields-new-agent-for-some-drug-resistant-non-small-cell-lung-cancers.html

Novel nanotechnology heals abscesses caused by resistant staph bacteria

Novel nanotechnology heals abscesses caused by resistant staph bacteria

New three-drug combination for multiple myeloma ! ...

The regimen, known as RVD, combined the drugs Revlimid - (lenalidomide), Velcade - (bortezomib) and dexamethasone, which previously were found to be highly effective in multiple myeloma patients who had relapsed or no longer responded to first-line therapies.

Fifteen of the 35 newly diagnosed patients in the open-label phase 2 portion of the study subsequently underwent autologous (using their own blood-forming stem cells) transplants, a standard treatment for multiple myeloma and did very well.

For the entire group, after a median 19.3 months of follow up, the median time-to-progression (TTP) of the disease, progression-free survival (PFS), and overall survival (OS) had not yet been reached, according to the presentation. The estimated TTP and PFS at one year are 76 percent, and the estimated one-year overall survival is 100 percent, the results showed.

The more interesting part of the study is that the high response rate was not affected by the specific genetic characteristics of the patients' disease. Patients with so-called "adverse cytogenetics" are at higher risk for treatment failure and death, but in the current study the drug combination worked as well for them as it did in patients with more favorable cytogenetic features.

Except for the main adverse effect, peripheral neuropathy (numbness or pain in the extremities), which typically cleared up after dosages were lowered and the treatment was completed.

The combination has now gone into large phase 3 clinical trials, and the researchers think that this regimen has the potential to be a new standard of treatment in multiple myeloma....

http://www.dana-farber.org/abo/news/press/2009/multiple-myeloma-patients-experience-high-response-rate-with-new-three-drug-combination.html

Apremilast a new hope for severe Psoriasis...

About apremilast :

(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethyl]- 1,3-dioxo - 2,3 -dihydro - 1H-isoindol-4-yl}acetamide.

Apremilast, is a member of a proprietary pipeline of novel small molecules with anti-inflammatory activities that inhibit the production of multiple proinflammatory mediators including, PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase.

Now Celgene announces positive data from its apremilast Phase IIb study for plaque-type psoriasis.

As per the claim by the company, 41% of patients treated with 30mg of oral apremilast BID achieved a PASI-75 after 16 weeks (p<0.001).

Ref : :http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1365878&highlight=

Treprostinil as IV infusion reduces breathlessness in PAH patients...

The treatment, continuous intravenous (IV) treprostinil, (see structure, the drug has already been approved by the U.S. Food and Drug Administration for the treatment of pulmonary arterial hypertension PAH) based on its similarity to an approved treatment delivered subcutaneously (directly into the skin). Practicing physicians, had hesitated to endorse the treatment because it did not have its own placebo-controlled study. But now the researchers from University of Rochester Medical Center, have come up with interesting results.

The more interesting part of their research is that PAH patients had higher than normal blood levels of factors known to play central roles in the clogging of arteries as part of major diseases like atherosclerosis and hypertension, including angiopoietin-2 (Ang-2) and platelet derived growth factor. Treatment with treprostinil was associated with lowers levels of Ang-2.

Though the mode of action has to be established (relaxing muscles surrounding blood vessels for easier blood flow and turning off sticky ingredients that cause blood clots e.g. platelets) , its is a good achievement. Treprostinil-treated patients feel like they are breathing easier because their lung arteries, not the lungs themselves, are working more efficiently. Better understanding of the mechanisms involved may lead to refinements in drug design; for example, blocking the effects of Ang-2 to treat the disease (may be easier on patients than a continuous IV infusion). Though further studies are essential, its a good achievement and hope in the days to come people with PHT will definitely breathe a sigh of relief instead of breathlessnessssss.....

Source : http://www.urmc.rochester.edu/news/story/index.cfm?id=2711

FDA approves Olanzapine as Extended Release Injectable Suspension.....

In continuation of my update on drug development for schizophrenia , am sharing this info. The U.S. Food and Drug Administration (FDA) approved ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension for the treatment of schizophrenia in adults. Different from both oral and injected short-acting formulations, long-acting formulations of antipsychotics allow for stable concentrations of the active drug to remain at a therapeutic range for an extended period of time.

The FDA approval is based on a broad clinical data package involving 2,054 patients, in which ZYPREXA RELPREVV was found to be effective in controlling symptoms of schizophrenia, including hallucinations, delusions, apathy and social withdrawal. Efficacy was shown without the need for oral supplementation. Clinical data showed that ZYPREXA RELPREVV dosages (150, 210, 300 and 405 mg) provide therapeutic olanzapine exposure for two or four weeks depending on the dose. More interesting outcome from these trials is that ZYPREXA RELPREVV was found to have a similar safety profile as oral olanzapine, with the exception of injection-related events, including post-injection delirium/sedation syndrome (PDSS).

PDSS events have occurred in < 0.1 percent of injections and approximately 2 percent of patients. The potential for onset of an event is greatest within the first hour after injection. The majority of cases have occurred within the first three hours after injection; however cases have occurred after three hours. All patients largely recovered within 72 hours.....

Ref : http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=429876

Synthetic platelets halt blood-clotting time....

Lavik and co workers made platelets from polymers already used in treatments approved by FDA. They also built the parts of the synthetic platelets that bind to natural platelets from relatively short pieces of proteins (asthey're more stable than longer pieces and cheaper). To avoid formation of an artificial clot, each synthetic platelet is built with a surrounding water shield. Fluorescing compounds showed the synthetic platelets not bound in clots were flushed from the rat model's system in a day. No ill effects were seen in the following week......

More.....Synthetic platelets halt blood-clotting time

Nilotinib more efficiant over Imatinib for (Ph+ CML)....

Nilotinib (see structure) :

Nilotinib, in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor, approved as Tasigna in USA and the EU for drug - resistant chronic myelogenous leukemia (June 2006), resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor currently used as a first-line treatment.

In a recently held large clinical trial, nilotinib demonstrated greater efficacy over the current gold standard treatment, imatinib, in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase.

As per the claim by the researchers, in the first head-to-head study of these two oral treatments as initial therapy for this life-threatening leukaemia, nilotinib demonstrated statistically significant improvement over imatinib in key measures of effectiveness used in the trial. The trial showed that at 12 months, significantly fewer patients on nilotinib 300mg twice-daily progressed from the initial chronic phase of the disease to the later accelerated or blast crisis phases than those on imatinib 400mg once-daily. This demonstrates that nilotinib provided significantly better control of the disease compared to imatinib.

95% of patients with CML have an abnormality known as the Philadelphia chromosome. This chromosome produces a type of protein called Bcr-Abl, which is responsible for the overproduction of the cancerous white blood cells that are the main feature in Ph+ CML. Nilotinib is a potent and selective inhibitor of the Bcr-Abl protein, thereby inhibiting the production of these cancerous cells.

Ref : http://www.novartis.com/newsroom/media-releases/en/2009/1359764.shtml

Lidocaine IV injection as pain killer after ambulatory surgery ?

We know that, Lidocaine or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.

Now researchers from University of Virginia, Charlottesville, have come up with interesting info about the same drug. As per the claim by the researchers low doses of lidocaine given intravenously can help to control pain after common ambulatory surgery procedures. Intravenous lidocaine may offer a safe, inexpensive, and effective option for improving pain control after minimally invasive or minor surgery, reports the new study led by Dr Danja S. Groves of University of Virginia, Charlottesville. The results are surprising, because local anesthetics such as lidocaine are usually injected close to the nerve to numb the area for surgery. Though the anestheas (higher dose) are toxic, previous studies have found that that IV lidocaine injection is safe in small doses. Though the mode of action and anti inflammatory activity are still to be expalined, is a good achievement...

Ref : http://www.newswise.com/articles/view/559452/

Combination of Lapatinib and Trastuzumab a better treatment for breast cancer....

Lapatinib or lapatinib ditosylate is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer. Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer. On March 13, 2007, FDA approved lapatinib in combination therapy for breast cancer patients already using capecitabine.

Recently, researchers from Duke University Medical Center. Dr. Kimberly Blackwell have found more interesting results when they did try the combination of Trastuzumab (monoclonal antibody). As per the claim by the researchers, Lapatinib plus trastuzumab are significantly better than lapatinib alone in extending the lives of breast cancer patients whose tumors are HER2-positive.

Blackwell says, the combination targeted therapy gave patients more than a four-month survival advantage over those who took lapatinib alone. She says the findings may be the first step toward a chemotherapy-free future. This is the first time that a pair of targeted therapies has been shown to be superior to any intervention that paired a targeted therapy with a hormonal or chemotherapy based approach, she said. The interesting claim by the researchers trastuzumab binds to and blocks part of the HER2 growth factor that appears on the surface of some breast cancer cells while lapatinib binds to a second growth factor, EGFR, and part of HER2 that sits below the cell surface. It's sort of a double whammy, disabling the HER2 protein in two places instead of one......

Ref : http://www.dukehealth.org/health_library/news/targeted_therapy_prolongs_life_in_patients_with_her2_positive_breast_cancer

Methotrexate & Ocrelizumab combination a new hope for RA patients....

In recent days, I have seen many researchers are trying the combination of existing drugs in combination with a monoclonal antibodies for many diseases like cancer, rheumatoid arthritis and are successful too. As synthetic chemist I was interested in knowing about these monoclonal antibodies and found some interesting info, which I am sharing herewith...

About monoclonal antibodies :

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given almost any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab.

The invention is generally accredited to Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975; who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. In 1988 Greg Winter (Nat Rev Cancer 2001;1:118-129) and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. Interestingly, many monoclinical antibodies have been tried for rheumatoid arthritis, chrohn's disease and as anticancer agents.

Many monoclonal antibodies like infliximab, etanercept and adalimumab were tried for the rheumatoid arthritis now its interseting to note that Genentech and Biogen Idec reported positive outcome from ocrelizumab ( humanized anti-CD20) -MTX (Methotrexate - see the structure : this drug is a part of DMARD treatment meant for RA patients) combination study in RA. The results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis. Hope patients suffering from RA and those are not responding will breathe a sigh of relief in the days to come...

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487

Bisphosphonates play a role in reducing recurrent breast cancer....

We know that bisphosphonates (also called diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. Bone has constant turnover, and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts digesting bone. Bisphosphonates inhibit the digestion of bone by osteoclasts. Osteoclasts also have constant turnover and normally destroy themselves by a process called cell suicide (apoptosis). Bisphosphonates encourage osteoclasts to undergo apoptosis. Though other uses like in he treatments of osteoporosis, osteitis deformans, bone metastasis, primary multiple myeloma,hyperparathyroidism and osteogenesis imperfecta were known. A new data suggests that these agents may play a role in reducing recurrent breast cancer as well. Zoledronic acid (see the structure) is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option.

As per the claim by the researchers lead by Dr. Adam Brufsky , women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection. More interestingly, in the same conference a research group lead by Rowan Chlebowski presented a study wherein "women who used bisphosphonates, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. .......

http://www.upci.upmc.edu/news/upci_news/121009_study.cfm

Xanthohumol may help in preventing prostate cancer....

We know that Xanthohumol is a Xanthone (phenylated chalcone or Phenylflavonoid). Xanthohumol was initially detected in an extract(series of Humulones) from Hops (Humulus lupulus) and is present in beer. This prenylated flavonoid has been shown to be a potent bioactive compound. Xanthohumol has been shown to have antiproliferative and cytotoxic effects in human cancer cell lines. It has also been displayed to inhibit diacyl glycerol acetyl transferase (DGAT) and human P450 enzymes. Xanthohumol inhibits the expression of HIF-1a and VEGF under hyposic conditions.

Higher antioxidant activity is reported for prenylchalcones than for prenyl flavanones in the Cu2+- mediated oxidation of LDL, suggesting a relation between structure and function. Also, many chalcones suppress tumor promotion more effectively than flavonoids themselves.

Quantities of xanthohumol found in Hop are to small to have any biological effects under normal consumption amounts. Some of the researchers also claims that it has got anti-HIV-1 activity too.

Now researchers from German Cancer Research Center, in Heidelberg, Germany, have come up with more interesting result, i.e., Xanthohumol may aid in preventing prostate cancer. As per the claim by the authors, the compound blocks the effects of the male hormone testosterone.

Studies to date have shown that xanthohumol blocks the action of estrogen by binding to its receptor, which may lead to prevention of breast cancer. Since testosterone receptors act similarly to that of estrogen — by binding, then stimulating hormone-dependent effects, such as gene expression and cell growth — the researchers examined whether xanthohumol might not only block the effects of estrogen, but also of the male hormone androgen. Xanthohumol prevented the receptor from translocating to the cell nucleus, thus inhibiting its potential to stimulate the secretion of PSA and other hormone-dependent effects.

The interesting part of their research is the molecular modeling results, which showed that xanthohumol directly binds to the androgen receptor structure. The researchers suggest that this compound may have beneficial effects in animals — when they measured the anti-androgenic potential of xanthohumol in a rat model, they found that although xanthohumol was not able to prevent an increase in prostate weight after testosterone treatment, it could reduce testosterone-increased seminal vesicle weight.

As per the claim by the researchers the prostate weights were not changed, xanthohumol still reduced the effects of hormone signaling, such as gene expression, measured in the prostate tissue...

Ref : http://mct.aacrjournals.org/content/1/11/959.full

Carfilzomib for multiple myeloma ?

The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. Therefore the researchers evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor - Carfilzomib.

The second-generation proteasome inhibitor carfilzomib is showing noteworthy response rates and low levels of adverse side effects among multiple myeloma patients in a phase II clinical trial.

The updated data from the 17-site study focuses on patients with relapsed or resistant multiple myeloma who have received one to three prior therapies, but not the drug bortezomib, the original proteasome inhibitor. The results are of grat importance because of the fact that multiple myeloma is an incurable, challenging disease with devastating consequences. While new agents are extending life expectancies, they often have adverse side effects, including severe neuropathy. Carfilzomib is showing good response rates, with an improved side effects, except for minor, included fatigue, nausea and anemia.

Ref : http://bloodjournal.hematologylibrary.org/cgi/content/full/110/9/3281/F1

MSRA can be stopped before it becomes dangerous ....

In continuation of my update on MRSA (methicillin-resistant Staphylococcus aureus), I found the following info interesting.

C. Jeffrey Brinker research group has determined that the very first stage of staph infection, when bacteria switch from a harmless to a virulent form, occurs in a single cell and that this individual process can be stopped by the application of a simple protein (as against the belief that, staph infections are caused by many bacterial cells that signal each other to emit toxins. The signaling process is called quorum sensing). The most significant results from the researchers are :

1. isolation of Staphylococcus aureus bacteria in individual (isolation of an individual bacterium
previously had been achieved only computationally);

2. demonstration of release of signaling peptides from a single cell, not a quorum &

3. introduction of an inexpensive, very low-density lipoprotein (VLDL) to bind to the
messenger peptide, they stopped the single cell from reprogramming itself.

One aspect of experimental rigor was the team's ability to organize living cells into a nanostructured matrix. The researchers has already done it with yeast, and just extended the process to bacteria. Researchers are optimistic about finding a mechanism to locate bacteria reprogramming in the body so that the antidote can be delivered in time. If they achieve what they are optimistic, so there will selectivity of targeting the bacteria (human gastro-intestinal system contains many useful bacteria) which in my opinion will be a remarkable feat....

Ref : http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.264.html

Anticancer & Antiinflammatory properties of Lunasin (Soy Peptide) established ?...

We know that many researchers have tried to establish the anticancer activity of the peptide lunasin (which has been already accepted as neutraceutical agent). Now researchers from University of Illinois have come up with more interesting facts, Soy peptide often discarded in the waste streams of soy-processing plants, may have important health benefits that include fighting leukemia and blocking the inflammation that accompanies such chronic health conditions as diabetes, heart disease, and stroke.

The researchers confirmed lunasin's bioavailability in the human body by doing a third study in which men consumed 50 grams of soy protein--one soy milk shake and a serving of soy chili daily-for five days. Significant levels of the peptide in the participants' blood give us confidence that lunasin-rich soy foods can be important in providing these health benefits.

In the cancer study, de Mejia's group identified a key sequence of amino acids- arginine, glycine, and aspartic acid, (the RGD motif)--that triggered the death of leukemia cells by activating a protein called caspase-3. The scientists also verified lunasin's ability to inhibit topoisomerase 2, an enzyme that marks the development of cancer, and they were able to quantify the number of leukemia cells that were killed after treatment with lunasin in laboratory experiments.

More interesting out come of their study is lunasin's potential anti-inflammatory activity, (first time) they showed that lunasin blocked or reduced the activation of an important marker called NF-kappa-B, a link in the chain of biochemical events that cause inflammation. They also found statistically significant reductions in interleukin-1 and interleukin-6, both important players in the inflammatory process (the reduction in interleukin-6 was particularly strong). As per the claim by the group, although the high cost of obtaining lunasin from soy waste limits its use for nutritional interventions, soy flour does contain high concentrations of the peptide (depending on some genotype soy).

Its good see the diverse activities associated with Soy......

Source : http://pubs.acs.org/doi/abs/10.1021/jf803303k?prevSearch=Elvira%2Bde%2BMejia&searchHistoryKey=

Discovery Of Novel New Class of Antimicrobial Agents... ......

We know that most of the bacteria are getting resistant to the present drugs and there is an urgent need to find a solution for resistant bacteria. Inn this global fight against resistant bacteria many companies are trying different ways and now Chaperone Technologies, Inc has come up with something innovative and interesting way, i.e., the company is trying to develop antimicrobial compounds that work by inhibiting bacterial hsp70 proteins (an entirely new mechanism of action).

Chaperone’s antimicrobial program focuses on development of peptide as well as small molecule hsp70 inhibitor drugs that block the effect of this important class of molecular “chaperones” whose role is to help mediate or respond to toxic misfolded proteins within bacteria. Inhibition of this critical bacterial protein has been proven to kill bacterial pathogens. Besides antimicrobials, the inhibition of hsp70 molecular chaperone proteins present in other cell-types has a range of therapeutic applications that are being investigated by the company.

Using sophisticated computerized molecular modeling techniques, proprietary high-throughput screening tools developed by Chaperone and other approaches, the company has significantly expanded its library of novel hsp70 inhibitor compounds including CHP-267 and CHP-281, just two of the many promising drug candidates from this highly promising family of small molecule inhibitors discovered by the Company. Chaperone is looking at hsp70 inhibitors as stand alone antimicrobial agents as well as in combination with other antimicrobials (e.g., Finafloxacin.HCl : see the structure -which is under phase II clinical trials). The company recently received a US Patent covering a method of significantly amplifying the effectiveness of other antimicrobials by combining their use with that of an hsp70 inhibitor. Combining a bacterial hsp70 inhibitor with another antimicrobial yields increased bacterial killing of clinically important pathogens and the potential for combination therapy.

Chaperone’s drug candidates have been proven effective against dangerous bacteria such as MRSA, acinetobacter, and vancomycin resistant enterococci. When combined with other antibiotics, Chaperone’s compounds stimulate powerful antibiotic synergy, providing superior efficacy even while using significantly lower doses of the combined agents.

Source : http://www.biospace.com/news_story.aspx?NewsEntityId=118501

Combination of EGCG & DAPH-12 - a treatment for brain disorders ?

Amyloid plaques are tightly packed sheets of proteins that infiltrate the brain. These plaques, which are stable and seemingly impenetrable, fill nerve cells or wrap around brain tissues and eventually (as in the case of Alzheimer's) suffocate vital neurons or brain cells, causing loss of memory, language, motor function and eventually premature death.

To date, researchers have had no success in destroying plaques in the human brain and only minimal success in the laboratory. One reason for these difficulties in finding compounds that can dissolve amyloids is their immense stability and their complex composition.

Yet, Dr. Duennwald ( Boston Biomedical Research Institute , BBRI) and co workers from Pennsylvania School of Medicine, experienced success in previous studies when he exposed amyloids in living yeast cells to EGCG (see the above structure). Furthermore, he and his collaborators also found before that DAPH-12, (see below structure) too, inhibits amyloid production in yeast.

About EGCG :

Epigallocatechin gallate, also known as Epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid and a type of catechin. EGCG is the most abundant catechin in most notably tea, among other plants, and is also a potent antioxidant and that may have therapeutic properties for many disorders including cancer. It is found in green tea, but not black tea, as EGCG is converted into thearubigins in black teas. EGCG can be found in many supplements.

These findings are significant because it is the first time a combination of specific chemicals (EGCG & DAPH-12) has successfully destroyed diverse forms of amyloids at the same time.

Though the detailed mechanism is still to be established, its a good achievement and hope this combinatorial therapy will help those sufferings from Alzheimer's and other degenerative diseases (Huntington's, and Parkinson's) in the days to come.....

Ref : http://www.nature.com/nchembio/journal/v5/n12/pdf/nchembio.246.pdf

Nizatidine as an Oral Solution.....

About Nizatidine :

Nizatidine is a histamine H₂-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). It was developed by Eli Lilly and is marketed under the trade names Tazac and Axid.


Recently FDA approved the Nizatidine Oral Solution in the 15 mg/mL strength. Nizatidine Oral Solution is the first available generic in oral solution form and marks Amneal’s fourth liquid approval. It represents the company’s first exclusive generic – Amneal has 180-day exclusivity to market the product beginning from the date of first shipment......

Source : http://www.amneal.com/headlines/archive/Nizatidine_Oral_Solution_12-04-09.pdf

Statins may protect against GVHD complications

Statins may protect against GVHD complications

First live targeting of tumors with RNA-based technology

Researchers at Duke University Medical Center have devised a way they might deliver the right therapy directly to tumors using special molecules, called aptamers, (Aptamers are oligonucleotides or peptide molecules that bind to a specific target molecule) which specifically bind to living tumor tissue.......

More....First live targeting of tumors with RNA-based technology

CASD-NMR a boon to structure validation....

CASD-NMR(Critical Assessment of Automated Structure Determination) of Proteins is a rolling community-wide experiment involving developers of software tools / protocols for the automated calculation of protein structures from NMR data. The goal of CASD-NMR is to help advance the relevant methodology in order to reach the level of quality and reliability required for direct structure deposition in the PDB. CASD-NMR will also produce extensive data sets that will be useful to develop better methods for NMR structure validation. The more significance of this project is : In the future, automation in NMR will allow 'unsupervised' results to be accepted by the community as being correct and viable, ready for inclusion in the Protein Data Bank (PDB) straight away. The PDB is a database that stores macromolecular structural data that is freely and publicly available for further research.

Ref : http://www.e-nmr.eu/CASD-NMR

New target for diabtes type 2 treatment ?

Mitochondria provide energy for cellular activity. Mitochondrial damage causes people with type 2 diabetes to lose insulin-producing cells, a finding that could lead to new treatments, researchers say.

The researchers (Dr. E. Dale Abel, chief of the endocrinology and metabolism division at the University of Utah School of Medicine in Salt Lake City) found that when insulin-producing beta cells in the pancreas can't respond to circulating insulin, it triggers a "molecular cascade" that damages the normal action of a certain molecular receptor on the surface of the mitochondria. The damaged mitochondria then begin to destroy adenosine triphosphate, the prime fuel for cellular activity. As a result, the beta cells die.

The study provides novel insights into the role of insulin signaling in the regulation of the BAD/GK complex, glycolytic enzyme activity and mitochondrial metabolism in pancreatic β-cells. Ser112-BAD_S and its upstream kinases may be potential targets for the maintenance of the BAD/GK complex that is necessary for normal mitochondrial function and the regulation of β-cell survival....

Source : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007983

CCII capsules offer safe and effective treatment for rheumatoid arthritis

Chicken collagen can provide relief from rheumatoid arthritis (RA) symptoms. A randomised, controlled trial, published in BioMed Central's open access journal Arthritis Research & Therapy, has found that Chicken type II collagen (CCII), a protein extracted from the cartilage of chicken breast, is a safe and effective treatment for RA.

More....CCII capsules offer safe and effective treatment for rheumatoid arthritis

Positive data from rose bengal disodium for psoriasis & atopic dermatitis....

Acid Red 94, (Rose Bengal sodium salt), 3,4,5,6-tetrachloro-2-(2,4,5,7-tetraiodo-6-oxido-3-oxoxanthen-9-yl)benzoate :

Provectus Pharmaceuticals, Inc announced preliminary data for the company’s PH-10 Phase 2 clinical trial for Psoriasis as well as for its Phase 2 clinical trial for Atopic Dermatitis. As per the claim by the company, in its Phase 2 trial of PH-10 (0.001% Rose Bengal) for psoriasis, preliminary data shows that 79% of 29 subjects in the clinical trial demonstrated improvement in the Psoriasis Scoring Index (PSI) during four weeks of daily treatment with PH-10. In addition, 83% of the subjects reported no or only mild pruritus (itching) by week four of the trial, with no significant safety issues noted. The 30^th and final subject will complete final evaluation in early December.

In its Phase 2 trial of PH-10 for atopic dermatitis (“eczema”), preliminary data from the first 18 subjects indicated that 94% of subjects had improvement in the Eczema Area Severity Index (EASI) during four weeks of treatment. Subjects applied PH-10 daily for up to four weeks to skin areas affected by atopic dermatitis, with response observed weekly throughout this treatment phase and for one month after the end of this period. As in the psoriasis study, the treatments were generally well tolerated with no significant safety issues identified. Hope a sigh of relief for those suffering from psoriasis and atopic dermatitis....

Ref : http://www.pvct.com/pressrelease.html?article=20091201

Positive Results from Chronic Study of Rivaroxaban (anticoagulant drug)...

Rivaroxaban, is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. If approved by the United States FDA, it will be marketed by Ortho-McNeil Pharmaceutical. It is the first available orally active direct inhibitor of coagulation Factor Xa. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs three hours after a dose. The effects lasts 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

Rivaroxaban is undergoing review by the FDA, On March 19, 2009, an advisory panel recommended FDA approval of rivaroxaban 10 mg once daily for use in patients undergoing hip or knee replacement surgery. The advisory panel concluded that the record trials demonstrate that rivaroxaban is non-inferior and possibly superior to subcutaneous enoxaparin 40 mg once daily. However, they also found an increased risk of bleeding with rivaroxaban and did not address the question of long-term (i.e. > 35 days) use. The advisory panel noted that 1 participant out of 6183 randomized to rivaroxaban died of liver toxicity.....

Source :http://abstracts.hematologylibrary.org/cgi/content/abstract/112/11/436?maxtoshow=&HITS=50&hits=50&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&displaysectionid=Oral+Session&fdate=1/1/2008&tdate=12/31/2008&resourcetype=HWCIT