Merck's Phase III trial assessing fracture risk reduction with odanacatib..

Merck announced   an update on the Phase III trial assessing fracture risk reduction with odanacatib, (a cathepsin K/cat-K inhibitor see structure below). The Data Monitoring Committee (DMC) for the study recently completed its first planned interim analysis for efficacy and recommended that the study be closed early due to robust efficacy and a favorable benefit-risk profile. As a result, Merck will begin taking steps to close the trial. The DMC noted that safety issues remain in certain selected areas and made recommendations with respect to following up on them. Merck's previously announced plan to conduct a blinded extension trial will allow further monitoring of the issues. The extension trial will also continue to measure efficacy.    

Merck anticipates submitting regulatory applications for approval of odanacatib in the U.S., European Union (EU) and Japan in the first half of 2013.

"We are encouraged by the Data Monitoring Committee's recommendation to close the trial early," said Peter S. Kim, Ph.D., executive vice president, Merck and president,

Merck Research Laboratories, "and look forward to reviewing the data with the scientific community to bring forward this innovation."

Drug from Mediterranean weed kills tumor cells in mice

The drug G202 is chemically derived from a weed called Thapsia garganica that grows naturally in the Mediterranean region. The plant makes a product, dubbed thapsigargin (see the structure,  that since the time of ancient Greece has been known to be toxic to animals. In Arab caravans, the plant was known as the "death carrot" because it would kill camels if they ate it, the researchers noted.

Thapsigargin is, 

(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-(acetyloxy)-4-(butyryloxy)-3,3a-dihydroxy-3,6,9-trimethyl-8-{[(2Z)-2-methylbut-2-enoyl]oxy}-2-oxo-2,3,3a,4,5,6,6a,7, 8, 9b-decahydro azuleno[4,5-b]furan-7-yl octanoate)

"Our goal was to try to re-engineer this very toxic natural plant product into a drug we might use to treat human cancer," says lead study author Samuel Denmeade, M.D., professor of oncology, urology, pharmacology and molecular sciences. "We achieved this by creating a format that requires modification by cells to release the active drug."

By disassembling thapsigargin and chemically modifying it, the researchers created a form that Denmeade likens to a hand grenade with an intact pin. [Thapsigargin prodrug G-202, is a cytotoxic analog of thapsigargin, 8-O-(12Aminododecanoyl)-8-O debutanoylthapsigargin (12-ADT) linked, via a carboxyl group, to the targeting peptide containing aspartic acid].

The drug can be injected and can travel through the bloodstream until it finds the site of cancer cells and hits a protein called prostate-specific membrane antigen (PSMA). PSMA is released by cells lining tumors of the prostate and other areas, and in effect "pulls the pin" on G202, releasing cell-killing agents into the tumor and the blood vessels that feed it, as well as to other cells in the vicinity. Specifically, G202 blocks the function of a protein called the SERCA pump, a housekeeping protein necessary for cell survival that keeps the level of calcium in the cell at the correct level, the researchers report.

"The exciting thing is that the cancer itself is activating its own demise," says senior study author John Isaacs, Ph.D., professor of oncology, urology, chemical and biomedical engineering at Johns Hopkins.

Because the drug is targeted to the SERCA pump, which all cells need to stay alive, researchers say it will be difficult for tumor cells to become resistant to the drug, because they cannot stop making the protein.

More : http://stm.sciencemag.org/content/4/140/140ra86

Drug from Mediterranean weed kills tumor cells in mice

Cranberry products associated with prevention of urinary tract infections

Use of cranberry-containing products appears to be associated with prevention of urinary tract infections in some individuals. 

Chih-Hung Wang, M.D., of National Taiwan University Hospital and National Taiwan University College of Medicine, and colleagues reviewed the available medical literature to reevaluate cranberry-containing products for the prevention of UTI.

"Cranberry-containing products tend to be more effective in women with recurrent UTIs, female populations, children, cranberry juice drinkers, and people using cranberry-containing products more than twice daily," the authors note.

The authors identified 13 trials, including 1,616 individuals, for qualitative analysis and 10 of these trials, including 1,494 individuals, were included in quantitative analysis. The random-effects pooled risk ratio for cranberry users vs. nonusers was 0.62, according to the study results.

"In conclusion, the results of the present meta-analysis support that consumption of cranberry-containing products may protect against UTIs in certain populations. However, because of the substantial heterogeneity across trials, this conclusion should be interpreted with great caution," the authors conclude.

More..

Cranberry products associated with prevention of urinary tract infections

Tolfenamic acid appears to reduce esophageal tumors

A new study by researchers at MD Anderson Cancer Center Orlando finds that Tolfenamic acid (TA, see structure), a non-steroidal anti-inflammatory drug (NSAID), commonly used to relieve pain, inflammation and migraines has now been found to reduce esophageal tumors.

The study, led by Pius Maliakal, PhD and Riyaz Basha, PhD, researchers at MD Anderson Orlando's Cancer Research Institute, found that Tolfenamic acid prevented tumor growth and lessened the size of esophageal tumors in a rat model. Tolfenamic acid has been found to decrease certain proteins that are critical for cancer cell growth and the progression of esophageal tumors.

MD Anderson Orlando researchers are at the forefront of Tolfenamic acid research. It was this same research team that found that Tolfenamic acid inhibits tumor growth in pancreatic cancer. MD Anderson Orlando is poised to begin a new Phase I Clinical Trial for pancreatic cancer patients using Tolfenamic acid in a few months.

Further research will be required before Tolfenamic acid can be used as a safe and effective drug for esophageal cancer prevention. At present, this drug is an approved anti-inflammatory agent in Europe, South America and Asia, but is not yet approved for use in the United States.

Tolfenamic acid appears to reduce esophageal tumors

Eltrombopag can raise blood cell levels in some people with severe aplastic anemia

Eltrombopag, a drug that was designed to stimulate production of platelets from the bone marrow and thereby improve blood clotting, can raise blood cell levels in some people with severe aplastic anemia who have failed all standard therapies.

About one-third of aplastic anemia cases do not respond to standard therapy, a combination of immune-suppressing drugs. Although bone marrow stem celltransplantation is an option for some, patients without a matched donor have few treatment options. The findings of this new clinical study, carried out by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, suggest eltrombopag (see structure) could be a second-line therapeutic option for them.

Aplastic anemia is a rare blood disorder, with about 600 new cases in the U.S. each year. Aplastic anemia results from the destruction of bone marrow stem cells, which mature into red blood cells that carry oxygen, white blood cells that fight infection, and platelets that prevent excess bleeding. Symptoms of the disorder include fatigue, frequent infections, and hemorrhaging. In severe cases unresponsive to treatment, death can occur.

The research team in the NHLBI Hematology Branch tested eltrombopag because this drug had previously been shown to boost platelet levels in both healthy people and people with reduced platelets due to hepatitis C infection or immune thrombocytopenia, blood disorders that like aplastic anemia result in low platelet counts and increased risk of bleeding.

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa073275

New Drug, Bedaquiline to Tackle Resistant TB

Johnson & Johnson said that it is seeking U.S. approval for the first new type of medicine to fight deadly tuberculosis in more than four decades.

The experimental drug, called bedaquiline (discovered by Koen Andries, see structure), also would be the first medicine specifically for treating multi-drug-resistant tuberculosis. That's an increasingly common form in which at least two of the four primary TB drugs don't work.

Mode of action : Bedaquiline affects the proton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase

Tuberculosis, caused by bacterial infection of the lungs and other body areas, is the world's No. 2 killer of adults among infectious diseases.

J&J's Janssen Research & Development unit created the drug, which was tested in several hundred patients with multidrug-resistant tuberculosis in two mid-stage studies lasting for six months. Some patients were studied for about 1 1/2 years.

The company this fall is to begin late-stage testing that will compare bedaquiline to dummy pills over nine months in about 600 patients; each will also take six other drugs that are the standard treatments for tuberculosis. That study is aimed at seeing whether treatment for resistant tuberculosis can be reduced to nine months from the current 18 to 24 months recommended by the World Health Organization.

Roughly one-third of the world's population is estimated to be infected with the bacteria causing tuberculosis. It remains latent in most people for many years but can be activated by another infection or serious health problem.

TB is rare in the U.S. but kills about 1.4 million people a year worldwide, with about 150,000 of those succumbing to the increasingly common multidrug-resistant forms.

Janssen's head of infectious diseases, Dr. Wim Pays, said the company will also apply for approval of bedaquiline in other countries where TB is very common.

The disease is a serious problem in developing countries because it takes so long to cure and many patients stop taking their pills once they begin to feel better. That helps bacteria still alive in the patient to develop resistance to the medicines already taken, making future treatment much more difficult.

Ref : http://www.inpharm.com/news/173302/janssen-submits-tuberculosis-pill-fda

Strawberry extracts actively stimulate proteins that offer protection against cardiovascular disease

In continuation of my update on benefits of strawberries...

Professor Paul Thornalley from Warwick Medical School heads the team that discovered extracts from strawberries positively activate a protein in our bodies called 'Nrf2' which is shown to increase antioxidant and other protective activities. This protein works to decrease blood lipids and cholesterol, the very things which can lead to cardiovascular problems.

Eating strawberries has previously been found to counter post-meal blood glucose and low density lipoprotein, or 'bad' cholesterol and therefore decrease risk of diabetes and heart disease, but this is the first time that strawberry extracts have been proved to actively stimulate proteins that offer us protection against disease.

Professor Thornalley explained:

"We've discovered the science behind how strawberries work to increase our in-built defences to keep cells, organs and blood vessels healthy and which can reduce the risk of developing cardiovascular problems such as heart disease and diabetes.

"So don't feel guilty about serving up strawberries and cream … although I'd suggest more strawberries and less or even no cream!"

Screening and mathematical modelling techniques developed at the University of Warwick can now take this research further to help identify the best varieties of strawberries, how they are served or processed and how many strawberries should be eaten for optimum health benefit.

Game, set and match to strawberries

Arena Pharmaceuticals and Eisai Announce FDA Approval of BELVIQ® (lorcaserin HCl) for Chronic Weight Management in Adults who are Overweight with a Comorbidity or Obese (NASDAQ:ARNA)

In continuation of my update on lorcaserin

Arena Pharmaceuticals and Eisai Announce FDA Approval of BELVIQ® (lorcaserin HCl) for Chronic Weight Management in Adults who are Overweight with a Comorbidity or Obese (NASDAQ:ARNA)

Enoxaparin prevents PVT in advanced cirrhosis

In continuation of my update on Enoxaparin

Enoxaparin (see structure) significantly reduces portal vein thrombosis (PVT) and increases overall survival in patients with advanced cirrhosis, the results of an Italian study show. The authors also found additional benefits beyond the drug's established effect on PVT.

The study included 70 cirrhosis patients with a Child-Pugh score of 7-10, aged 18-75 years who received enoxaparin 4000 IU/day for 48 weeks or no treatment. Patients were followed up for a mean of 58 weeks in the control group and 89 weeks in the enoxaparin group, with ultrasound evaluation of the portal vein system every 3 months.

As reported by the authors, patients receiving enoxaparin were 90% less likely to experience PVT than those who did not. Overall, 8.8% of enoxaparin-treated patients developed PVT compared with 27.7% in the control group, and no cases developed in the enoxaparin group within the first 2 years.

While decompensation occurred at an equal rate in both groups during the follow-up period, significantly fewer patients experienced progression during active treatment (11.7 vs 59.4%).

 Enoxaparin prevents PVT in advanced cirrhosis

FDA Approves Myrbetriq...

“Myrbetriq (see below structure) is the first oral OAB treatment with a distinct mechanism of action since the launch of anticholinergic agents 30 years ago,” said Steven Ryder, MD, president, Astellas Pharma Global Development. “The approval of Myrbetriq represents an important milestone in OAB treatment and in our ongoing commitment to advancing urological health.”....

FDA_Approval_Press_Release_FINAL 6.28.12.pdf (application/pdf Object)

Lexicon announces results from two initial trials of LX4211 for type 2 diabetes

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 (see structure) enhanced urinary glucose excretion by

inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA1c; and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

SGLT1/SGLT2 inhibition

Lxicon announces results from two initial trials of LX4211 for type 2 diabetes: Lexicon Pharmaceuticals, Inc. announced today the publication of results from two initial trials of LX4211 in patients with type 2 diabetes in the online edition of the journal Clinical Pharmacology & Therapeutics.

Provectus Pharmaceuticals - ASCO 2010

 We know that,

Rose Bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a stain. Its sodium salt is commonly used in eye drops to stain damaged conjunctival and corneal cells and thereby identify damage to the eye. The stain is also used in the preparation of Foraminifera for microscopic analysis, allowing the distinction between forms that were alive or dead at the time of collection.

A form of Rose Bengal is also being studied as a treatment for certain cancers and skin conditions. The cancer formulation of the drug, known as PV-10, (see the structure) is currently undergoing clinical trials for melanoma and breast cancer. The company also has formulated a drug based on Rose Bengal for the treatment of eczema and psoriasis; this drug, PH-10, is currently in clinical trials as well.

 Top-line final data from Provectus’ PV-10 phase 2 trial on metastatic melanoma

Provectus Pharmaceuticals - ASCO 2010

Study links carcinogens to cancer stem cells – but spinach can help | News & Research Communications | Oregon State University

In continuation of my update on spinach

Study links carcinogens to cancer stem cells – but spinach can help | News & Research Communications | Oregon State University

Xalkori Helps Lung Cancer Patients | News | Drug Discovery and Development Magazine

In continuation of my update Crizotinib/Xalkori 

Pfizer Inc. said its lung cancer drug Xalkori helped lung cancer patients who had previously been treated for the disease.

Pfizer said Xalkori (see the structre)  worked better than two older cancer drugs in the late-stage clinical trial. All patients had a rare type of non-small cell lung cancer and had previously been treated. The Food and Drug Administration approved Xalkori in August for use in patients whose cancer had not been treated.

In the study, patients took Xalkori, Alimta, or Taxotere. Pfizer said patients who took Xalkori had greater progression-free survival, or time from the start of treatment until they died or experienced disease progression. Xalkori is a pill taken twice per day while Alimta and Taxotere are given intravenously.

Xalkori is approved for use against non-small cell lung cancer in patients who have an abnormal gene that causes tumor growth. Xalkori blocks that gene, which is found in 1 percent to 7 percent of non-small cell lung cancer. About 85 percent of lung cancers are the non-small cell variety...

More...

Xalkori Helps Lung Cancer Patients | News | Drug Discovery and Development Magazine

Anacardic acid can rescue some ALS phenotypes in vitro...

A research group at the Center for iPS Cell Research and Application (CiRA) at Japan's Kyoto University has successfully recapitulated amyotrophic lateral sclerosis (ALS)-associated abnormalities in motor neurons differentiated from induced pluripotent stem cells (iPSCs) obtained from patients with familial ALS, a late-onset, fatal disorder which is also known for Lou Gehrig's disease. In a drug screening assay using the disease model, the team further found that the chemical compound anacardic acid (see structure)  can rescue some ALS phenotypes in vitro. 

Ref : http://www.cira.kyoto-u.ac.jp/e/pressrelease/news/120801-195947.html