PARP inhibitor, MK-4827, shows anti-tumour activity in first trial in humans....

MK-4827 , (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride.

A recent study claim that the new drug MK-4827 (see structure), that targets proteins responsible for helping cancer cells to repair damage to their DNA has shown promising anti-tumor activity in its first trial in humans. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year.

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2  (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. As per the claim by the researchers, drug act by inhibiting the action of PARP, double-strand breaks occur, leading to cell death. Researchers add that tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells don't replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

The researchers saw anti-tumor responses in both sporadic and BRCA1/2 mutation-associated cancers. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

More...

Study suggests pomegranate juice can ward-off complications in kidney disease patients

Study suggests pomegranate juice can ward-off complications in kidney disease patients

Novel iron complexes (quinoxaline) as potential antitubercular agents...

A team of researchers from Spain and Latin America have synthesized two iron compounds(complex with qunoxaline derivative below structure)  that inhibit the in vitro growth of Mycobacterium tuberculosis, the bacteria that causes tuberculosis. Due their low level of toxicity in mammel cells, the compounds could be used in the future as therapeutic agents and hospital disinfectants.  

As per the claim by the researchers, the complexes are better than the second line drugs (we know already about drug resistant tubercular species and tuberculosis is being considered as re-emerging disease due to the increase in the number of people with HIV and other viruses that attack the immune system, as well as to the increasing consumption of immunosuppressive and recreational drugs).  Another advantage of the iron compounds is that they show low toxicity in mammal cells, as demonstrated by the experiments performed with mice cells.

"That is why these compounds are useful as hospital disinfectants or therapeutic agents," the Uruguayan researchers highlight, albeit recalling that, at present, they in vitro trials "and the line of research remains open to learn more about how they act."

Researchers conclude that, the novel complexes showed in vitro growth inhibitory activity on Mycobacterium tuberculosis H₃₇Rv (ATCC 27294), together with very low unspecific cytotoxicity on eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M. tuberculosis than the “second-line” therapeutic drugs....

Ref : Dinorah Gambino et.al., Journal of Inorganic Biochemistry Volume 104, Issue 11

Trends in drug discovery for Alzheimer's disease.....

In continuation of my update on Alzheimer' disease and drug discovery...

We  know that Alzheimer’s disease(named after Dr. Alois Alzheimer. In 1906) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimer’s, symptoms first appear after age 60. 

Alzheimer’s disease is the most common cause of dementia(loss of cognitive functioning—thinking, remembering, and reasoning to such an extent that it interferes with a person’s daily life and activities) among older people. Dementia is the  Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer’s and Alzheimer's is predicted to affect 1 in 85 people globally by 2050. 

Future drugs for Alzheimer’s disease : 

Thirty years ago, we knew very little about Alzheimer’s disease (with four medications approved so for...). Since then, scientists have made many important advances. Research supported by NIA and other organizations has expanded knowledge of brain function in healthy older people, identified ways we might lessen normal age-related declines in mental function, and deepened our understanding of the disease. Many scientists and physicians are now working together to untangle the genetic, biological, and environmental factors that, over many years, ultimately result in Alzheimer’s. This effort is bringing us closer to the day when we will be able to manage successfully or even prevent this devastating disease.

A recent research survey claim that, symptomatic market will remain active in this disease. New symptomatic entrants to the market will include Aricept patch and the first-in-class 5-HT6 receptor antagonist SB-742457.  Datamonitor forecasts that the current late-stage pipeline will yield three blockbusters, but this is by no means guaranteed considering the high risk of failure in Phase III Alzheimer’s disease trials. Of the pipeline drugs, Datamonitor believes that bapineuzumab(an antibody to the beta-amyloid (Aβ) plaques) and solanezumab (a humanized antibody that binds to soluble ß-amyloid and thereby may draw the peptide away from the brain through the blood and this could reduce the formation of amyloid plaque)have the most commercial and clinical potential. Research survey conclude that value of the Alzheimer’s disease market across the seven major markets was $4.7bn in 2009 and is forecast to reach $11.9bn by 2019. More....

 

Asthma Drug Prevents Spread of Breast Cancer, Study Finds......

We know that. Tranilast (structure, brand name Rizaben) is an antiallergic drug. It was developed by Kissei Pharmaceuticals and was approved in 1982 for use in Japan and South Korea for bronchial asthma. Indications for keloid and hypertrophic scar were added in 1993. It has been used for the treatment of allergic disorders such as asthma, allergic rhinitis and atopic dermatitis. It has been also reported that it reduces (in-vitro) collagen synthesis in fibroblasts, inhibits the growth of neurofibroma cells and inhibits ( in-vitro) the production of interleukin-6 in endothelial cells.

Now researchers from St. Michael's Hospital, Canada reports that the drug to stop the spread of breast cancer cells traditionally resistant to chemotherapy.

Researchers grew breast cancer stem cells, which give rise to other cancer cells, in culture. The cells were injected into two groups of mice, including one group, which was also treated with tranilast. Dr. Prud'homme and his colleagues found the drug reduced growth of the primary cancerous tumour by 50 per cent and prevented the spread of the cancer to the lungs. Researchers also identified a molecule in the cancer cell that binds to tranilast and appears to be responsible for this anti-cancer effect.

As per the researchers 'Tranilast' binds to a molecule known as the aryl hydrocarbon receptor (AHR), which regulates cell growth and some aspects of immunity. This makes the drug beneficial in treating allergies, inflammatory diseases and cancer.

"For the first time, we were able to show that tranilast shows promise for breast cancer treatment in levels commonly well-tolerated by patients who use the drug for other medical conditions," Dr. Prud'homme said. "These results are very encouraging and we are expanding our studies. Further studies are necessary to determine if the drug is effective against different types of breast and other cancers, and its interaction with anti-cancer drugs.........

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013831

Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

Recently, I did write an article regarding the future of antisense drugs for BlogNotions (wherein I did mention about the Regulus plans for mRNA platform)...


Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

Chillies for diabetes: Study

In continuation of my update on diabetes and its treatment,  I find the following study interesting.  In fact, I had a blog article  , where in the authors claim that Capsaicin may cause weight loss and I think these findings are of great significance........

Chillies for diabetes: Study

 

FDA approves Pradaxa to prevent stroke in people with atrial fibrillation....

We knew that, Dabigatran (see structure, Pradaxa in Europe and USA, Pradax in Canada) is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in many cases it offers an alternative to warfarin as the preferred orally administered blood thinner since it does not require prothrombin time monitoring while offering similar results in terms of efficacy. It was developed by the pharmaceutical company Boehringer Ingelheim. Though it was approved in Europe in 2008, now FDA has approved the drug in October 2010 for the prevention of stroke and blood clots in patients with abnormal heart rhythm (atrial fibrillation).

Pradaxa is an anticoagulant that acts by inhibiting thrombin, an enzyme in the blood that is involved in blood clotting. The safety and efficacy of Pradaxa were studied in a clinical trial comparing Pradaxa with the anticoagulant warfarin. In the trial, patients taking Pradaxa had fewer strokes than those who took warfarin.

 "Unlike warfarin, which requires patients to undergo periodic monitoring with blood tests, such monitoring is not necessary for Pradaxa," Dr. Norman Stockbridge(director of the Division of Cardiovascular and Renal Products in the FDA's ) says.

Pradaxa, manufactured by Boehringer Ingelheim Pharmaceuticals Inc. of Ridgefield, Conn., will be available in 75 milligram and 150 milligram capsules....

Ref : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm

Study finds anti-obesity drug reduces brain’s response to appetizing foods

Sibutramine (usually in the form of the hydrochloride monohydrate salt) is an oral anorexiant. Until recently it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in the US, EU, AU etc. 

Sibutramine is a centrally-acting serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines, although its mechanism of action is distinct.

Now, researchers lead by Prof. Paul Fletcher at the University of Cambridge discovered that the anti-obesity drug sibutramine reduced brain responses in two regions of the brain, the hypothalamus and the amygdala, both of which are known to be important in appetite control and eating behavior.

Using functional magnetic resonance imaging (fMRI), the researchers measured brain activity while obese volunteers viewed pictures of appetising high-calorie foods - like chocolate cake - or pictures of low-calorie foods - like broccoli. The brain scanning was carried out both after two weeks of treatment with the anti-obesity drug, sibutramine (see structure above), and two weeks of placebo treatment. 

On placebo, it was shown that simply seeing pictures of appetising foods caused greater activation of many regions of the brain that are known to be important for reward processing. On sibutramine, however, they found that the anti-obesity drug reduced brain responses to the appetising foods in two regions of the volunteers' brain - the hypothalamus and the amygdala. These two regions are known to be important in appetite control and eating behaviour. Additionally, people who had the greatest reduction of brain activation following drug treatment tended to eat less and to lose more weight.

I quote....

"The most exciting aspect of these results is that they help us to see that brain and behaviour are fundamental to understanding and treating obesity. Simply because obesity involves major changes in body weight and body composition, it is easy to imagine that it is entirely 'a body problem'. These results remind us that the major cause of obesity in the West is over-eating, and this behaviour is regulated by reward and satiety processing circuits in the brain." 

Ref : Paul C. Fletcher et. al., The Journal of Neuroscience, October 27, 2010

Effective treatment for brain cancer in daffodils.............

We know that, Daffodil is a common English name, sometimes used now for all varieties of Narcissus genus, and is the chief common name of horticultural prevalence used by the American Daffodil Society.

Its use in medicinal use has been reported, in kampo (traditional Japanese medicine - wounds were treated with narcissus root and wheat flour paste), listed in De Medicina (among medical herbs, described as emollient, erodent, and "powerful to disperse whatever has collected in any part of the body). However in one scientific study, the ethanol extract of the bulbs was found effective in one mouse model of nociception, para-benzoquinone induced abdominal constriction, but not in another, the hot plate test.

Now researchers lead by Robert Kiss from Institute of Pharmacy at the Universit- Libre de Bruxelles in Brussels, Belgium, have come up with an interesting findings i.e., a natural compound found in daffodil bulbs, called narciclasine (see structure below) , may be a powerful therapeutic against biologically aggressive forms of human brain cancers.

To make this discovery, Kiss and colleagues used computer-assisted techniques to identify targets for narciclasine in cancer cells. The strongest potential candidate to emerge was the eEF1A elongation factor. Researchers then grafted human melanoma brain metastatic cells into the brains of genetically altered mice. Results showed that the injected mice survived significantly longer when treated with narciclasine than those mice left untreated. The researchers believe that narciclasine selectively inhibits the proliferation of very aggressive cancer cells, while avoiding adverse effects on normal cells. Narciclasine could be used in the near future to combat brain cancers, including gliomas, and metastases such as melanoma brain metastases.....

Ref : http://www.fasebj.org/content/24/11/4575.abstract