Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets ..

Suspecting that a particular protein in tuberculosis was likely to be vital to the bacteria's survival, Johns Hopkins scientists screened 175,000 small chemical compounds and identified a potent class of compounds that selectively slows down this protein's activity and, in a test tube, blocks TB growth, demonstrating that the protein is indeed a vulnerable target.

 

This class of chemical compounds attacks TB by inhibiting methionine aminopeptidase (MetAP), an essential enzyme found in organisms ranging from bacteria to humans, and that clearly has been conserved throughout evolution because of its important task of ensuring the proper manufacture of proteins.

Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, researchers overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. 

 

Researchers screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. As per the claim by the researchers, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis and they conclude  that MtMetAP1a is a promising target for developing antituberculosis agents.

 

The scientists cautioned that although the MetAP inhibitors prevent TB growth in test tubes, they have a long way to go before being declared safe and effective to treat TB patients...

 

"Judging from potency, a MetAP inhibibitor alone probably won't wipe out TB," Liu says. "TB is so hard to treat that the standard therapy involves a cocktail of multiple drugs; no single compound is powerful enough. Our hope is that someday an inhibitor of MetAP will become a new component to enhance the existing therapy."

Ref : Jun O. Liu et.al., Chemistry & Biology, Volume 17, Issue 1, 29 January 2010, Pages 86-97

Clinical Data completes NDA submission for vilazodone.......

         Vilazodone (structure) is an antidepressant and anxiolytic of  the piperazine chemical class.

Clinical Data, Inc.   recently announced that the Company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for vilazodone for the treatment of major depressive disorder (MDD). Vilazodone is a dual-acting potent and selective serotonin reuptake inhibitor and a 5-HT_1A receptor partial agonist. The Company expects that the NDA submission, if accepted, will be subject to a standard review. 

This is a major milestone in the development of vilazodone and, if approved, its dual mechanism of action and safety profile will offer a new alternative for patients suffering from depression,” said Carol R. Reed, M.D..more...

Gemcitabine and cisplatin a promising combination for endometrial cancer...

In continuation of my update on cis-platin and its importance, I find this  info interesting to share with...

Gemcitabine (see structure) and cisplatin in combination have been investigated extensively in other disease sites, and synergism of the two agents has been confirmed in cell lines of human endometrial, ovarian, colon, lung and squamous cell head and neck carcinoma

Now researchers from The University of Texas M. D. Anderson Cancer Center , lead by Dr.Jubilee Brown, report from a small study of women with advanced or recurrent endometrial cancer, that gemcitabine and cisplatin, when used in combination, produced a response rate in fifty percent of patients.

The Phase II study of 20 patients found that the combination of gemcitabine and cisplatin, two drugs currently used to treat other types of cancer, limited the disease's progression, increasing progression-free survival while maintaining tolerable toxicity levels. It is believed that when administered together, gemcitabine helps overcome cell resistance to cisplatin, throwing tumor cells a potent one-two punch.


Findings demonstrated a 50 percent overall response rate, or improvement in disease. Additionally, the clinical benefit of the two-drug combination was 80 percent, as 16 of the 20 women experienced either an improvement or stabilization of disease. All side effects resulting from the therapy were manageable. Lead researcher, Dr. Brown concluded  that results from the study warrant investigation of the chemotherapy combination in a larger, definitive trial at multiple institutions.....

Ref :  Dr. Jubilee Brown, http://www.mdanderson.org/

New study finds green tea extract may prevent Alzheimer's disease and dementia

In continuation of my update on green tea benefits......

New study finds green tea extract may prevent Alzheimer's disease and dementia

Salsalate may be useful for the treatment of patients with type 2 diabetes .....

We know that Salsalate (see structure; source Drugs.com)  is a  non-steroidal anti-inflammatory drug (NSAID) belonging to salicylates. It is used in the treatment of Osteo Arthritis and  Rheumatoid Arthritis. 

Now researchers from Harvard Medical School, lead by Dr. Allison Goldfine, have come up with interesting finding, i.e., Salsalate may be useful for the treatment of patients with type 2 diabetes as well. In a three-month trial of people with type 2 diabetes ,  those who took the drug showed significantly improved blood glucose levels. 

Starting off, the patients all had levels of hemoglobin A1C (a standard measurement that reflects blood sugar levels over several months) in the range of 7.0 to 9.5%. A significant number of those who took salsalate saw this number drop by 0.5%, a result that is in the range of several recently released diabetes therapeutics. Other tests related to glucose levels also showed substantial improvement.  

Overall the drug appeared to be safe and to be tolerated well by patients. The study included 108 individuals, aged from 18 to 75 years, at 17 clinical sites around the United States. Patients were randomly divided into four; three groups were each given differing amounts of salsalate in three daily doses, while the fourth received placebos. All patients continued with their current regimes for managing diabetes.

Though these preliminary findings  suggests  that,   salsalate may provide an effective, safe and inexpensive new avenue for diabetes treatment, however the researchers  want to complete the ongoing  additional studies so that they can further substantiate their claim........

Ref : March 16 in the Annals of Internal Medicine

Study provides better understanding of how mosquitoes find a host......

In continuation of my update on on developments in mosquito repellents ......

The potentially deadly yellow-fever-transmitting Aedes aegypti mosquito detects the specific chemical structure of a compound called octenol as one way to find a mammalian host for a blood meal, Agricultural Research Service (ARS) scientists report".......

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007032....

Eprotirome a promising addition to statin therapy ?

People with bad cholesterol have  risk of  future heart disease,  despite  cholesterol-lowering statin therapy. Now researchers from  Johns Hopkins have come up with interesting finding i.e.,  a drug that mimics the action of thyroid hormone [Eprotirome (new generic name for KB2115) structure source : chemBlink)  lowered cholesterol up to 32 percent in those already on statins, an effect equal to that expected from doubling the statin drug doses, without harmful side effects. 

Interestingly, the researchers caution that the results don't suggest that eprotirome will or should replace statins, which are the current gold standard for treating high LDL cholesterol.

However, the results of their small trial on 168 patients do suggest that eprotirome may eventually be a promising addition to statin therapy, a substitute for statins in people who can't tolerate their side effects, or a novel treatment for mixed dyslipidemia, a condition in which people have high levels of lipids other than cholesterol such as triglycerides or apolipoprotein B (apo B).

The researchers found that among the patients taking the 25, 50 or 100 mg doses of eprotirome reduced their LDL cholesterol levels by 22 percent, 28 percent, and 32 percent respectively, compared to only 6.5 percent in those taking placebo. Remarkably, they also found similar dose-related reductions in triglycerides, apo B, and Lp(a). They also found modest reductions in HDL cholesterol of approximately 3 percent.

As per the claim by the lead researcher Dr. Paul W. Ladenson,   'this drug represents a new class of medications that might offer hope to those at risk of future cardiovascular disease whose lipid profiles are not effectively altered with statin therapy, and perhaps for about a quarter of those who have tried statins but cannot tolerate their side effects'. Dr. Ladenson is a consultant to Karo Bio, maker of eprotirome.......

Ref : http://content.nejm.org/cgi/content/short/362/10/906

From carnivorous plants to the medicine cabinet? Anti-fungal agents in pitcher plants investigated

Carnivorous plant : Nepenthes khasiana (see picture)......

From carnivorous plants to the medicine cabinet? Anti-fungal agents in pitcher plants investigated.....

Positive phase III efficacy clinical trial for Fentanyl sublingual spray .....

INSYS Therapeutics, Inc. announced positive results from the pivotal phase III efficacy  trial for patients utilizing the Fentanyl Sublingual Spray (SL Spray) technology to treat breakthrough cancer pain.  The company claims that all primary and secondary endpoints were achieved in the study, and the drug is the first product to ever show statistically significant pain relief when measuring the summary of pain intensity difference at five minutes (SPID(5)) in a phase III breakthrough cancer pain trial using Fentanyl.

Dr. Richard Rauck, a principal investigator in the Phase III study observed,  the sublingual spray demonstrated very rapid, effective pain relief. Patients began to experience meaningful pain relief within five minutes. This observation was supported by the clinical research findings.  As claimed by the researchers, to date, no other transmucosal Fentanyl  (see the general structure) product has produced pain relief this quickly. This  finding is supported with continued pain relief at all subsequent time intervals. 

Hope this easy-to-use oral spray that can produce effective, potent and very rapid pain relief will be a tremendous advantage for the  patients who experience moderate to severe cancer breakthrough pain.....

Ref : http://www.insysrx.com/news.htm

Japanese patent for Archexin (a novel anti-cancer drug)....

Rexahn Pharmaceuticals, Inc., a clinical stage pharmaceutical company commercializing potential best in class oncology and CNS therapeutics, announced that the Japanese Patent Office has issued a patent for its novel anti-cancer compound, Archexin. As per the claim by the company,  Archexin is a first in class, potent inhibitor of Akt protein kinase in the treatment of cancer. 

The AKT pathway is an important therapeutic target for cancer drug discovery as it functions as a main point for transducing extracellular and intracellular oncogenic signals. Moreover, alternations of the AKT pathway have been found in a wide range of cancers. Akt regulates signal processes of cell proliferation and survival, angiogenesis, and drug resistance in cancer. Archexin is being developed to treat solid tumors and has FDA Orphan drug designation for RCC, pancreatic, stomach, glioblastoma, and ovarian cancers. Archexin is in Phase II clinical development for pancreatic cancer as lead indication.

Archexin(R) was fromerly named as RX-0201, is  an oligonucleotide compound that  inhibits the expression of human Akt-1. I am really happy for this approval because, in my opinion this will boost the new field of drugs (ologonucleotides/antisense). I have covered some developments in this field, those interested can read earlier articles...

Combination therapy (Dutasteride & Tamsulosin) more effective for enlarged prostate...

Researchers from UT Southwestern Medical Center, lead by  Dr. Claus Roehrborn have come out with something interesting finding, i.e., two drugs  (Dutasteride, see left structure)  and Tamsulosin (see below structure) commonly prescribed for enlarged prostate yielded better results than either of the medicines alone.

The study, which included more than 4,800 men, is one of the first to compare single and combo medication regimens in such a large group.

 The first group of study participants received the drug dutasteride; the  second group received tamsulosin; and the third received a combination of the two medicines. Researchers found that, the combination therapy to be superior at reducing risk of BPH   progression   (25 % reduction in prostate volume). Interestingly, patients who received the combination therapy also showed a 50 percent reduction of prostate-specific antigen (PSA), a protein produced by both cancerous and noncancerous prostate tissue. 

Compared with tamsulosin alone, the combination of drugs reduced the incidence of acute urinary retention by 67 percent and reduced the need for BPH-related surgery by 70 percent.  They also  found  a 65 percent decrease in the relative risk of acute urinary retention or BPH-related surgery compared with tamsulosin alone and just over a 19 percent reduction compared with dutasteride alone.

Researchers conclude that  this research should provide physicians better information when they decide on a course of treatment for patients with BPH.....

Ref :  http://www.utsouthwestern.edu/utsw/cda/dept353744/files/578603.html

Presentations on Geron's Telomerase Inhibitor at AACR Special Conference

In continuation of my update on Geron's Telomerase Inhibitor..... Geron Corporation, announced several presentations at the American Association for Cancer Research (AACR) Special Conference on The Role of Telomeres and Telomerase in Cancer Research held in Fort Worth, TX between February 27th and March 1st. The conference comprised ten scientific sessions with over fifty oral presentations.

Geron scientists and collaborators presented recent data on the company's telomerase inhibitor, imetelstat sodium (GRN163L), And highlighted the drug's activity against cancer stem cells. As per the claim by the CMO & EVP, Stephen M. Kelsey,   the telomerase inhibitor is showing anti-cancer stem cell activity in a range of preclinical models. In Phase II trials of imetelstat starting this year Greron is targeting malignancies that are thought to be driven, at least in part, by cancer stem cells ....

Ref: http://www.geron.com/media/pressview.aspx?id=1213

Maple Syrup and Maple water contain abscisic acid.....

It has recently been reported that maple syrup contains polyphenols  and shows ORAC (Oxygen Radical Absorbance Capacity, a unit of measurement for antioxidants developed by the NIH)  values which compare to commonly eaten fruits and vegetables such as broccoli. Now, further research on maple syrup and its original form, maple water, conducted by Dr Yves Desjardins and his colleagues (at  Institut des neutraceutiques et des aliments fonctionnels), has revealed that both products contain equally important quantities of terpenes, and in particular, abscisic acid (see structure), a phytohormone whose health benefits have only recently been discovered. 

Vegetable physiologists and botanical researchers have known about the physiological properties of abscisic acid in the vegetable kingdom for a long time, but its health benefits for humans has only recently come to light. Along with other effects, it is known to stimulate insulin release through pancreatic cells and to increase sensitivity of fat cells to insulin, which makes it a potent weapon against  metabolic syndrome and diabetes. So its good to see that maple products contain a whole host of complementary active elements. The sugar molecules which provide the energy and sweetness in maple products are inherently complemented by abscisic acid molecules because they encourage insulin homeostasis. 

The authors conclude that, further studies are obviously needed before one can more accurately understand how eating maple products affects insulin behavior......

Ref : Dr Yves Desjardins et.al., (Emerging Topics in Health Effects of Fruits and Vegetables symposium which forms part of the 28th International Horticultural Congress in Portugal, August 22-27, 2010.)

Oldest epilepsy drug (Ethosuximide) best for Children with "Petit Mal"....

Ethosuximide ( see structure)  is a succinimide anticonvulsant, used mainly in absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug Valproic acid. There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

Now researchers, lead by Dr. Tracy A. Glauser, Director of Comprehensive Epilepsy Center at Cincinnati Children's Hospital Medical Center, have come up with an interesting finding, i.e., ethosuximide (Zarontin), one of the oldest anti-seizure medications  is most effective at controlling what is called absence or "petit mal" epilepsy, with the fewest side effects. Valproic acid (Valproate, Depakote) came second, and the newest drug, lamotrigine (Lamictal), was third.

The study included children aged 2.5 to 13 years, newly diagnosed with epilepsy and free of other problems, such as autism. They were randomly assigned to one of the three drugs. The study measured primarily whether they were free of seizures without intolerable side effects after 16 weeks, with a few children continuing for as long as 20 weeks. The study also measured how the drugs affected the children's ability to pay attention.

Ethosuximide prevented seizures in 53 percent of the children, slightly less than the 58 percent freedom-from-failure rate of valproic acid but significantly better than the 29 percent for lamotrigine. But only 33 percent of those taking the older drug had significant attention problems, compared to 49 percent of those taking valproic acid, the researchers found. 

Researchers conclude that, it was somewhat unexpected that the oldest of the drugs had as good an effect as the other and better side effects &  the study highlights the importance of looking not only at seizure control but also how the child does otherwise.......

Ref : http://www.cincinnatichildrens.org/about/news/release/2010/epilepsy-trial-3-4-2010.htm

Cabazitaxel improves survival in patients with metastatic hormone-refractory prostate cancer....

Cabazitaxel (see structure), is an orally bioavailable semi-synthetic  derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB).

Sanofi-aventis recently announced results from a Phase 3 trial which demonstrated cabazitaxel plus prednisone/prednisolone significantly improved overall survival and progression-free survival in patients with metastatic (advanced) hormone-refractory prostate cancer whose disease progressed following treatment with docetaxel-based chemotherapy. 

TROPIC (trial) was designed to assess patients with metastatic hormone-refractory prostate cancer whose disease had progressed following treatment with docetaxel-based chemotherapy. Results showed that the combination of cabazitaxel and prednisone/prednisolone significantly reduced the risk of death by 30%.

Researchers are  happy with these compelling results  and  hope that these results will provide new options and hope for patients with serious diseases, such as metastatic hormone-refractory prostate cancer.....

Ref : http://en.sanofi-aventis.com/binaries/20100304_Asco_GU_en_tcm28-27547.pdf