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