New journal devoted to gene therapy...

As for as my knowledge goes there was no exclusive journal totally devoted to gene therapy until last year. Yeah its really interesting to to see "The Gene Therapy Review" a journal totally devoted to gene therapy. In my opinion it is an important move and was the urgent need of the hour. Now the fields like antisense drugs & gene therapy will get its due importance and hope in the days to come, will bring together all those people to share and gain the knowledge..... Those interested can follow the blog also.....

URL : http://www.genetherapyreview.com/index.php

Blog : http://www.genetherapyreview.com/gene-therapy-blog.html

Masitinib - a relief for arthritis patients ....

I know the sufferings of arthritis patients closely, (as my mother-in-law is having the problem) it makes patients' life miserable. Though there are a few drugs for the treatment, but are inadequate for patients suffering from active rheumatoid arthritis (RA) especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is need of the hour. In that aspect clinical trials of Mastineb, 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-thiazolyl] amino] phenyl]benzamide carried out by Alain Moussey et. al., is of great importance.

The study evaluates the safety and efficacy of Masitinib, a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.

We also know that, the orally bioavailable mesylate salt of masatinib, a multi-targeted protein tyrosine kinase inhibitor with potential antineoplastic activity selectively binds to and inhibits both the wild-type and mutated forms of the stem cell factor receptor (c-Kit; SCFR); platelet-derived growth factor receptor (PDGFR); fibroblast growth factor receptor 3 (FGFR3); and, to a lesser extent, focal adhesion kinase (FAK). As a consequence, tumor cell proliferation may be inhibited in cancer cell types that overexpress these receptor tyrosine kinases (RTKs), clinical trials also reported.

As per the conclusions by the authors, treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. Congrats for the group...

Antisense drug in combination with paclitaxel for prostate cancer..

I think when I was doing some reference work for my research in 1996, I read about this drug (taxol) [In 1994 the total synthesis has been achieved by Robert Holton of Florida University. He did spend 12 years to achieve the total synthesis because of the assymmtery involved in it [It was after 40 years' after the first exctract from the tree Pacific yew (Taxus brevifolia) has shown anticancer activity and the key ingrediant identified was taxiol]. A diterpenoid, with androgen (a male hormone) blockade chemotherapy has played important role in the treatment of cancer.

Prostate cancer is the second most frequently diagnosed cancer in men after skin cancer. It is estimated there will be 218,890 new cases diagnosed in the U.S. this year(2009). Around 1 in 6 men will develop prostate cancer, a third to a half of whom will recur after local treatment and risk progression to metastatic prostate cancer. Metastatic disease invariably progresses to hormone refractory or castrate resistantprostate cancer (CRPC) if given enough time.

Prostate tumours are initially androgen (male sex hormone) dependent, and can be treated with androgen ablation therapy, however once the disease progresses to its most dangerous and aggressive form, CRPC, treatment options are limited and prognosis is poor. Treatment options depend on disease severity and include radiation and chemotherapy, which are designed to induce programmed cell death (apoptosis) of tumour cells. There is a pressing need for the development of new treatment options.

More interesting and significant results have been achieved by an Australian company (Antisense Therapeutics). i.e., in combination with taxol, antisense drug ATL1101 has yielded good results. ATL1101 is a second generation antisense inhibitor of the insulin-like growth factor-I receptor (IGF-IR) which as reported previously suppressed the growth of human prostate tumors in an animal model of prostate cancer, and slowed down transition to CRPC when used as a single agent.

The research is of great importance because of the fact that in cell culture experiments, the amount of Paclitaxel required to induce tumor cell apoptosis (cell death) was significantly reduced when used in combination with ATL1101. This ability to 'sensitize' tumor cells to the cytotoxic effects of Paclitaxel affirms ATL1101's potential as a chemo-sensitizing agent to be used in combination with existing prostate treatments to improve the outcomes for patients.

I did work for some of the intermediates (ologonucleotides) for ISIS (contract research) and am excited to see that this company has tie up with ISIS. In my opinion as ISIS , is an established company in this field of research, hope soon there will be relief for those patients for whom CRPC, treatment options are limited and prognosis is poor....

Ref: http://www.antisense.com.au/!upload_files%5Cattachment%5Casx%2009%2018%20June%202009_ATL1101.pdf

Exenatide for weight reduction !...

Exenatide, ( 39-amino-acid peptide an insulin secreta gogue with glucoregulatory effects) a compound belonging to "incretin mimetics" was approved for the treatment of diabetes mellitus type 2 in April, 2005, but not for type 1.

Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster. It displays biological properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion. According to the package insert, exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying, although the mechanism of action is still under study.

Recently it has been found that along with the treatment for type 2, the compound has been found to reduce the weight of non diabetic obese people.

Michael Trautmann, MD, a Principal Investigator with Eli Lilly in Indianapolis, recently reported that in combination with diet and exercise, the diabetes drug exenatide helped nondiabetic, obese individuals lose over three times more weight than those receiving a placebo, or dummy treatment, for 6 months. Drug therapy is considered important adjunctive treatment to diet and exercise in the successful management of obesity, Trautmann said. "To date, however, there are few effective drugs that help obese people lose weight", which is very important fact. and as the drug is already an established one, the only side effect like mild or moderate nausea and diarrhea are to be taken care off.

As per the claims of the authors : individuals who received exenatide lost more weight in 24 weeks than controls did. Those who received the medication lost an average of more than 11 pounds (5.06 kg), whereas the controls lost just 3.5 pounds (1.61 kg). This difference was statistically significant and noted as early as week 8. Only exenatide-treated subjects lost more than 10 percent of their body weight (seven of 73 subjects, or 9.6%). The plausible explaination for the action of this drug is "decreased food intake and increased feelings of fullness". Congrats Dr.Mikeand group....[these findings are being presented in the The Endocrine Society's 91st Annual Meeting in Washington, D.C., June 10 - 13th, 2009.]

iNMR is software for Mac OS...

While reading a news article, I found this interesting info, as for the software providers' claim its the only software for Mac OS users. Its really nice, people who are using Mac OS, can visit the link and if interested can try...

Cisplatin doubles lung cancer survival time in mice !

When I was studying my M.Sc., (1992), we used to have a question regarding the anticancer activity of cisplatin and after that I could see lots of research in the field of anticancer activity. And so many new drugs have been established and are being used as drugs. Cisplatin works by crosslinking across DNA inter-strands, making it impossible for rapidly dividing cells to duplicate their DNA for cell division (mitosis). The damaged DNA sets off DNA repair mechanisms which fails to work, so in turn activate cell death processes (apoptosis). The trans isomer does not have this pharmacological effect.

After so many years, I could find this something interesting findings about cisplatin, by Patrizia Russo of Lung Cancer Unit of the National Cancer Research Institute in Genoa, Italy and colleagues from San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Catholic University.

In the study, the authors took the research a step further and showed that α-CbT could inhibit non-small cell lung carcinoma (NSCLC) growth and prolong life in non-obese/severe combined immunodeficient (NOD/SCID) mice that had human NSCLC grafted to their lungs. This study attempted to mimic human cancer conditions more closely by delaying treatment until the tumors were well-established. In addition to control mice that were untreated, the researchers randomized one third of the mice to receive standard chemotherapy.

They found that NOD/SCID mice treated with the standard chemotherapy agent, cisplatin, had a 16 percent longer median survival time than untreated mice (p= 0.05). Mice treated with α-CbT, however, had an increased median survival time of 1.7-fold over the cisplatin-treated mice and 2.1-fold over the no-treatment controls (p=0.0005). Though the clinical trials to establish the claim and to to explore the widest range of possibilities of intervention on the α7-nAChRs. Congrats...

Ref :Inhibition of Nonneuronal 7-Nicotinic Receptor for Lung Cancer Treatment; Am. J. Respir. Crit. Care Med., Jun 2009; 179: 1141 - 1150

FDA's approval of Injectable ibuprofen

We did know about the oral form of ibuprofen, now FDA has approved the injectable form of ibuprofen. Injectable ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) are promising pain management options said Dr. Bob Rappaport, Director, Division of Anesthesia, Analgesia and Rheumatology Drug Products in the FDA’s Center for Drug Evaluation and Research. But until now (as for as my knowldge goes, diclofenac sodium is being used), there were only oral forms of most NSAIDs. An injectable ibuprofen product can provide patients with relief from pain and fever when they cannot take oral product.

In a clinical trial of 319 women who had undergone an elective abdominal hysterectomy, patients were less likely to request morphine for pain on an as-needed basis when administered Caldolor.

Caldolor should be used with caution in patients with congestive heart failure, kidney impairment, at risk of blood clots and those who have a prior history of ulcers or gastrointestinal bleeding. When used in such patients, attention to using the lowest effective dose for the shortest time period is important to reduce the risk of serious adverse events. The drug has also been associated with high blood pressure, serious skin reactions, and serious allergic reactions. Though the side effects like nausea, flatulence, vomiting, and headache are being noticed during clinical trials. Its a good move becoz., the dose by IP route will be less and definitely reduce the risk of the ulcerogenecity (a common problem due to NSAIDs).

Ref : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm165971.htm

Silver nano particles as antiplatelet agent?

We know common side effects of anti-thrombotic agents [aspirin & Reo Pro (abciximab) ] like dangerous bleeding and ulcerogenecity (of aspirin) so there is an urgent need to have more safer antiplatelet agents. Now thanx to Debabrata Dash and colleagues of Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi for their innovative findings that is., now silver nano particles can be used as antiplatelet agent.

The scientists describe development and lab testing of silver nanoparticles that seem to keep platelets in an inactive state. Low levels of the nanosilver, injected into mice, reduced the ability of platelets to clump together by as much as 40 percent with no apparent harmful side effects. The nanoparticles "hold immense potential to be promoted as an antiplatelet agent," the researchers note. Nanosilver appears to possess dual significant properties critically helpful to the health of mankind — antibacterial and antiplatelet — which together can have unique utilities, for example in coronary stents. One more "Nano" to the drug discovery kitty. Congrats Dash and group for this achievement. More...

Telaprevir for Hepatitis C, soooon...

We did know that Telaprevir (VX-950), is a member of a class of antiviral drugs known as 'Protease Inhibitors' was an experimental treatment for Hepatitis and two companies Vertex and Johnson & Johnson jointly developed and phase II clinical trials were being done. Now thanx, to Dr. Ira M. Jacobson chief of the Division of Gastroenterology and Hepatology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and the Vincent Astor Distinguished Professor of Clinical Medicine at Weill Cornell Medical College, who has come up with the results of Phase IIb clinical trial.

Th results are really encouraging and as per the author, "the findings point the way to a new era in the treatment of hepatitis C". The most significant part of the research lies in the fact that, by adding Telaprevir the treatment was more effective and quicker and there by reducing the therapy to half (from 48 weeks to 24 weeks).

Results showed that 67 percent of patients taking telaprevir in combination with standard therapy for 12 weeks followed by standard therapy alone for 36 weeks were cured; and 61 percent of those taking telaprevir in combination with standard therapy for 12 weeks followed by standard therapy alone for 12 weeks were cured. This is compared to 41 percent cure rate in the 48-week control group. And more over the study also showed that the percentage of patients who relapsed in the 24-week and 48-week telaprevir-based groups (2 percent and 6 percent, respectively) was much lower than the control group (23 percent). Also the authors found that it can be used alongwith Ribavirin, for those with HIV & Hepatitis C. Congratulations for this achievement. Phase III clinical trials are currently underway at the NewYork-Presbyterian/Weill Cornell and centers worldwide will attempt to confirm the results, potentially leading to FDA approval of telaprevir and hope there will be a relief to the sufferers very soooon......

Ref : http://news.med.cornell.edu/wcmc/wcmc_2009/06_04_09.shtml

Pazopanib for aggressive thyroid cancer.

There were lots of research groups involved in testing Pazopanib for diverse anticancer activity like "epithelial ovarian cancer, non small cell lung cancer and GSK was the key researcher and did try the phase III clinical trials in other cancer types, in Sept., 2008. Now thanx, Dr. Keith Bible, a medical oncologist and researcher who led the multicenter clinical trial funded by the National Cancer Institute, for this significant findings - cancer in about two-thirds of 37 patients with aggressive differentiated thyroid cancer treated with the drug pazopanib either stopped growing, or quickly shrank. And as per the conclusions : one-third of patients achieved sustained and dramatic benefit from pazopanib, while another one-third experienced stabilization of their cancer or some tumor shrinkage. The remaining one-third of patients did not benefit from the drug. The agent was also well tolerated by the majority of patients. Though further studies like - drug's effect on overall survival still to be established its a good beginning.

As per the authors conclusion majority of the patients with thyroid cancer respond well to surgery and to follow-up treatment with radioiodine; even if the cancer recurs and spreads, the disease progresses slowly in most patients. Many patients do well for a long time without the need of additional therapy. However, about 5 percent of these patients experience rapidly progressing life-threatening disease that is insensitive to radioiodine and other treatment approaches and for them this treatment will be a good one, the researchers claim. Congrats Dr. Bible and group..

Ref : http://www.mayoclinic.org/news2009-rst/5272.html

Glutamine for stomach ulcer ?

We know that Glutamine is the most abundant naturally occurring, non essential amino acid in the human body and one of the few amino acids which directly crosses the blood brain barrier. In the body it is found circulating in the blood as well as stored in the skeletal muscles. It becomes conditionally essential (requiring intake from food or supplements) in states of illness or injury.

Dietary sources of L-glutamine include beef, chicken, fish, eggs, milk, dairy products, wheat, cabbage, beets, beans, spinach, and parsley. Small amounts of free L-glutamine are also found in vegetable juices and fermented foods, such as miso.

In one of my earlier blog, I did mention that broccoli, has been found useful against the H. pylori infection, now its the turn of Glutamine-that has been found useful against the infection. Dr. Susan Hagen, Associate Director of Research in the Department of Surgery at BIDMC and Associate Professor of Surgery at Harvard Medical School and group has found that extra glutamine in the diet could protect against gastric damage caused by H. pylori.

Gastric damage develops when the bacteria weakens the stomach's protective mucous coating, damages cells and elicits a robust immune response that is ineffective at ridding the infection. Eventually, she notes, years of infection result in a combination of persistent gastritis, cell damage and an environment conducive to cancer development. Dr. Hagen and her co-authors had previously shown that glutamine protects against cell death from H. pylori-produced ammonia. And further studies revealed that, the damaging effects of ammonia on gastric cells could be reversed completely by the administration of L-glutamine," explains Hagen. "The amino acid stimulated ammonia detoxification in the stomach - as it does in the liver - so that the effective concentration of ammonia was reduced, thereby blocking cell damage', which encouraged the group to hypothesize that a similar mechanism might be at work in the intact stomach infected with H. pylori.

The results are encouraging and are of great importance, because of the fact that the animals exhibited increased expression of three cytokines - interleukin 4, interleukin 10 and transforming growth factor-alpha mRNA. According to the authors these all play an important role in the stomach's ability to protect against damaging effects resulting from other responses to H. pylori infection. And more interestingly-glutamine supplementation may be an alternative therapy for reducing the severity of infection. Thus ptoviding a relief to the patients suffering from H.Pylori. H. pylori bacteria infect more than half of the world's population and were recently identified as a Group 1 carcinogen by the WHO. Hope this inexpensive, easy-to-use treatment could be used to modify the damaging effects of H. pylori infection inthe near future.
Congrats Dr. Susuan and group. ....

Ref : http://www.bidmc.org/News/InResearch/2009/May/StomachUlcers.aspx

Antiinflammatory activity of H2S gas !

Its something interesting, we knew that a gas which everybody hates and even lethal has been found to possess antiinflammatory activity by Dr. Matt Whiteman from the Peninsula Medical School. The research team investigated the role of H₂S in endotoxic shock, which causes a fatal loss of blood pressure and extensive tissue inflammation.

They discovered that when H₂S is delivered in a slow and sustained manner, a potent anti-inflammatory effect is produced. Cell signalling molecules that drive inflammation, such as TNFα, IL-1, IL-6 and prostaglandins, were reduced while levels of the body's own anti-inflammatory molecules (i.e. IL-10) were increased. We know the side effects of NSAIds and even the so called nonulcerogenic NSAIds have side effects (except for those with selectice inhibitors of 5-LO and CO), most of them have side effects. Hope the outcome of this research will lead to compounds which can overcome the side effects. Thus generating H₂S in a controlled and sustained manner offers the potential for the development of a new group of anti-inflammatory drugs or lead to the modification of existing drugs so they also release H₂S and hopefully come with less gastrointestinal side-effects.

Hope, using H₂S donating molecules to control H₂S delivery in the body could pave the way for the development of novel approaches to the treatment of inflammatory disorders. Congrats Dr. Matt Whiteman and his group for this interesting finding...

Mechanism of Antibiotic Resistance Explained !

We all know that the introduction of antibiotics as drugs in the treatment of bacterial infections in the post-WWII years was a revolutionized medicine, and dramatically improved the health condition on a global scale. 60 years later now, the growing antibiotic resistance among pathogens has heavily depleted the arsenal of entailed effective antibiotic drugs and especially in the case of TB, combination of 4 drugs is being used and don't know what happens ?. Now thanx to Prof. Måns Ehrenberg for his novel discovery i.e., inhibiting the "drug efflux pumps" in bacteria, which function as their defence mechanisms against antibiotics, can mask the effect of mutations that have led to resistance in the form of low-affinity drug binding to target molecules in the cell. This is shown by researchers at Uppsala University in a new study that can provide clues to how the development of resistance to antibiotics in bacteria can be delayed.

This new study, experimentally and theoretically explained how the inhibition of these drug efflux pumps can completely mask the resistance effect of mutations that reduce the affinity of antibiotics to their target molecules in the bacteria cell. The effect of the mutations is entirely hidden when the pumps are unable to remove the antibiotic sufficiently quickly in relation to the dilution of the antibiotic through cell growth and cell division.

A new way for drug discovery....

Ref : http://www.pnas.org/content/early/2009/04/30/0811514106.abstract?sid=4175ffe7-b04b-4fc3-9270-af9a9bd5d953

Auranofin an arthritis drug as new antibiotic?

Traces of mineral selenium is found in a number of proteins in both bacterial cells and human cells called selenoproteins. Associate Professor William Self's research shows that interrupting the way selenoproteins are made can halt the growth of the super bug Clostridium difficile and Treponema denticola, a major contributor to gum disease.

Infections of Clostridium difficile (C-diff) lead to a wide range of illnesses ranging from severe diarrhea to colitis, which can cause death. It's a life-threatening problem in hospitals and nursing homes worldwide, and the number of cases is on the rise. There are an estimated 500,000 cases per year in the US alone. Between 15,000 to 20,000 people die each year while infected with this superbug. Treponema denticola is one of leading causes of gum disease and costs individuals thousands of dollars in dental care each year.

The significance of the research lies in the fact that, the gold drug Auranofin used to treat arthritis, impacted selenium's metabolism process. The chemical reaction changes the selenium, which prevents bacteria from using it to grow. Auranofin is an FDA-approved gold salt compound that is used to control inflammation and is already known to inhibit the activity of certain selenoproteins. Since certain bacteria, such as C. difficile, require selenoproteins for energy metabolism, the drug acts as a potent antimicrobial halting the growth of the bacteria. The initial studies with C. difficile led to studies with T. denticola, known for several years to require selenium for growth. While testing the gold salt, Self's group also uncovered another surprise; the stannous salts found in many antimicrobial toothpastes in the form of stannous fluoride also inhibited the synthesis of selenoproteins. Previous independent research had already established that stannous salts are more effective at preventing tooth decay and inhibiting growth of T. denticola, but the mechanism of this inhibition of growth was not yet known. These findings could lead to new approaches to preventing gum disease. The out come of the research is really interesting because no one in the earlier days thought of this innovative idea, i.e., to block the metabolism of selenium before as a therapeutic approach. And also this may through some light how "gold salt works for arthritis". Congrats Prof. Self and co workers...

Ref :http://www.springerlink.com/content/g6725k414863446q/?p=1f9d7cac7a4e4867af336327382c16bd&pi=4

Aerosol delivery of antibiotics via nanoparticles !

These days we are hearing lots of news about "nano", I would say anything and everything is nano, now its the turn of drug delivery that too as "aerosol" form!. Though there were lots of research groups trying to do the nanoway, I think this is something really interesting. Carolyn L. Cannon, M.D., Ph.D. from Washington University School of Medicine, and colleagues from the Center for Silver Therapeutics Research at the University of Akron in OH investigated the efficacy of nanoparticle-encapsulated silver-based antibiotics for treating pulmonary infections in a mouse model of pneumonia.

Treatment with antibiotic-laden nanoparticles effectively eliminated respiratory infections in mice that had been inoculated with Pseudomona aeroginosa, a common bacterial species that often infects the respiratory tract in humans, particularly immunocompromised patients, ventilated patients or those with cystic fibrosis. Infected mice that inhaled aerosolized nanoparticles encapsulating silver carbene complexes (SCCs), a novel class of silver-based antimicrobials with broad-spectrum activity, showed a significant survival advantage over the control mice that received nanoparticles without the SCCs. The results are really interesting and even the half the dose is sufficient. Toxicity results are still to be done, however this is a good beginning and hope they will come up with interesting results in the near future...

Ref :http://www.thoracic.org/sections/publications/press-releases/conference/articles/2009/abstracts-and-press-releases/cannon.pdf