Latrepirdine (dimbon) may ease cognitive effects of Huntington's disease....

We know that Dimebon (latrepirdine), an investigational drug currently in  Phase 3 development, that halt the onset of advanced Alzheimer’s (AD) and dramatically improve the quality of life for patients. Dimebon has a unique mechanism of action, distinct from currently available treatments. In preclinical studies, dimebon has been shown to protect brain cells from damage and enhance brain survival, potentially stabilising and improving mitochondrial function.

Now researchers from School of Medicine and Dentistry at the University of Rochester in New York lead by Dr. Karl Kieburtz, have found that  Dimebon may improve thinking, learning and memory skills in people with Huntington's disease  an inherited neurodegenerative disorder. 

Mitochondria are critical to brain cell functioning as they are the primary source of energy for cells. Drugs that protect mitochondria or restore their function could potentially be a valuable treatment approach in AD and Huntington's disease.

As per the claim by the researchers, the drug stabilizes and improves the function of mitochondria, parts of cells that help convert food into energy. Researchers found that, Dimebon (Latrepirdine)  at a dosage of 20 mg three times daily, is well-tolerated for 90 days in patients with Huntington's disease and may have a beneficial effect on cognition. Though further studies are essential to substantiate the claim, its good to see at l(e)ast a drug for Huntington's disease (the only approved therapy for Huntington's is tetrabenazine, which treats movement problems but does not prevent cognitive decline or change the course of the disease).....more...

FDA approves Olmesartan (Benicar, Olmetec) for children....

Olmesartan (Benicar, Olmetec-by Ranbaxy) is an angiotensin II  receptor antagonist used to treat high blood pressure. 

Mode of action : Olmesartan works by blocking the binding of angiotensin II to the AT₁ receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike ACE inhibitors. By blocking binding rather than synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.

Now FDA has approved the hypertension treatment Benicar (olmesartan medoxomil) for use in children and adolescents 6 to 16 years of age.  Benicar was originally approved in 2002 for the treatment of hypertension in adults (Daiichi Sankyo, Inc.).

The approval of this expanded indication was based on a phase III study examining the antihypertensive effects of Benicar in pediatric patients. The study found Benicar to be safe and efficacious in children ages 6-16 with hypertension, resulting in blood pressure reductions that were statistically different in comparison to placebo. Benicar was generally well tolerated in pediatric patients, and the adverse event profile was similar to that for adults.

Ref : http://www.dsi.com/news/pdfs/FINAL_Benicar_Pediatric_Approval_Press_Release.pdf

Triapine with cisplatin a new standard of care for cervical cancer?

In continuation of my update on cancer drug development,   I found this  info interesting to share with. Researchers  lead by Dr. Charles Kunos at the Ireland Cancer Center of University Hospitals (UH)  have found that,  Triapine, (3-aminopyridine-2-carbox -aldehyde   thiosemicarbazone, see structure), which suppresses tumor growth shows a great deal of promise for cervical cancer patients who are at high risk for relapse and cancer-related death. 

The phase I study found that the chemotherapy medicine  Triapine, was well tolerated in combination with standard-of-care cisplatin chemotherapy and radiation treatment in women with cervical cancer. This regimen provided both significant reduction in cancer disease and cancer control.

In the study   (ten-patient study) patients,  were treated three times weekly with Triapine (a potent Ribonucleotide Reductase Inhibitor) in combination with weekly cisplatin treatment and daily pelvic radiation therapy over five weeks.  The researchers claims that  "a 100% complete response rate was observed and no disease progression was documented through 18 months of median follow-up."A phase two follow-up study is ongoing at the Ireland Cancer Center. UH Case Medical Center  Hope this new found combintaton will be  a promising new treatment to help women fight this aggressive disease in the days to come...

Ref : http://clincancerres.aacrjournals.org/content/16/4/1298.abstract?sid=f3df7c2d-9e46-4baf-b47b-83d310b87641

Enantioselective synthesis of Kinamycin F - a new hope for anticancer drug development ?

The kinamycins are a series of naturally occurring compounds endowed with intriguing molecular architectures and potent biological properties such as  antibiotic and antitumor activities. These novel diazofluorene-containing compounds defied chemical synthesis since their initial disclosure by Omura et al. in 1970 until the first total synthesis of kinamycin C by Porco et al. in late 2006.

Now, researchers from Yale University,  have  developed a new method to recreate this structure that allows them to synthesize the kinamycins with much greater efficiency than previously possible.

As per the claim by the researchers,  key to the success of the route was  the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure source : JACS) function of the natural product.

While scientists have produced kinamycins in the laboratory in the past, the Yale team was able to halve the number of steps required to go from simple, easily obtainable precursors to the complete molecule from 24 down to 12. 

This sequence comprises fluoride-mediated coupling of a β-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from (structure), have been postulated to form in vivo, and this approach provides a straightforward synthetic pathway to such compounds.

This research is of great importance because by shortening the synthesis one can now prepare these molecules in the quantities required for further studies, including animal studies and even clinical trials.

Working with researchers at the Yale School of Medicine and the Yale Chemical Genomics Screening Facility, the team has begun testing several of the compounds against cancer cells, with promising preliminary results. Next, they will work to understand the exact mechanism that makes the compounds,  which are benign on their own  highly toxic once they penetrate cells. Lead researcher Dr. Seth Herzon, says "the key to success will be whether they can develop selectivity - whether they can kill cancer cells in the presence of non-cancerous tissue". Dr.Herzon  is also optimistic about lomaiviticin A (which also has the reactive core kinamycin,  and is even more toxic and could prove even more effective in destroying cancer cells)...let us hope positive results from this study....

Ref : http://pubs.acs.org/doi/abs/10.1021/ja910769j 

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases

Hyperthermia-free TRPV1 antagonists - new category of pain killers?

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1), also known as the capsaicin receptor is a protein which in humans is encoded by the TRPV1 gene. This protein is a member of the TRPV group of transient receptor potential family of ion channels. TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best known activators of TRPV1 are heat greater than 43°C,  pepper like chemicals  (capsaicin - most of us might have used gel containing capsaicin) and proton. The same channel is responsible for pain caused by these diverse stimuli. For a number of years scientists have focused on the development of TRPV1 antagonists, but have been stymied by the dangerous hyperthermia side effect.

Now researchers lead by  Dr. Andrej A. Romanovsky,  have come up with an explanation for the side effect and how one can avoid the side effect. 

Researchers found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (–0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). Hence they conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia. Researchers suggests that the  drugs that are being developed should be designed not to block the proton activation of TRPV1.

Scientists believe that this new generation of painkillers will be effective in treating pain related to a number of conditions including cancer, AIDS, migraines and diabetes. Let us hope some good news from these class of compounds....

Ref : Abstract of the paper

Inhibition of serotonin synthesis in gut - a new way of treating osteoporosis ?

A crucial clue uncovered in Dr. Karsenty’s lab turned his attention to the small intestine, wherein his research team found that the gene Lrp5, (previously linked to a rare form of osteoporosis) controls the production of serotonin in the gut, and that serotonin is an inhibitor of bone formation. By inactivating Lrp5 in the small intestine of mice and thereby turning on the production of serotonin, bone mass decreased. While in contrast, the deletion of the same gene in the bone cells of mice, on the other hand, had no effect on bone mass. As per the claim by the researcher, these findings demonstrate that serotonin from the gut is acting as a hormone to regulate bone mass (1). 

Most osteoporosis drugs, including those currently under clinical investigation  do not generate new bone but prevent the breakdown of old bone and the only drug currently in  the market which can generate new bone   has its limited application (due to its reported increased risk of bone cancer,is restricted for short-term and  that too in women with severe osteoporosis). Researchers  read about an investigational drug, known as LP533401  which is able to inhibit serotonin in the gut they synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1)  the initial enzyme in GDS biosynthesis.

Results demonstrated that osteoporosis was prevented from developing, or when already present, could be fully cured (in mice). Interestingly  levels of serotonin were normal in the brain, which indicated that the compound did not enter the general circulation and was unable to cross the blood-brain barrier, thereby avoiding many potential side effects. Dr. Karsenty and his colleagues did not find any gastrointestinal problems in mice unable to produce serotonin in their guts, suggesting that a serotonin inhibitor would not produce any such side effects in humans. The authors conclude that these results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Ref : http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2098.html

New cyclopropane derivative as better antidepressant ?

We know that most of the antidepressants have side effects such as  constipation, dry mouth, drowsiness and hypotension, or low blood pressure. Amongst various trypes TCAs, tricyclic antidepressants also have  the above mentioned side effects. 

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), among others, though they are still sometimes prescribed for certain indications.

Duloxetine, is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and it is as effective as venlafaxine in generalized anxiety disorder. Duloxetine failed the US approval for stress urinary incontinence amidst the concerns about liver toxicity and suicidal events; however, it was approved for this indication in Europe and Canada.

Interestingly, chemists at Oregon State University have discovered and synthesized a new compound  (see the structure) that in laboratory and animal tests appears to be similar to, but may have advantages over Duloxetine. As per the claim by the  lead researcher Dr. James White (Professor Emeritus of Chemistry at OSU),  the new compound has properties similar to (Cymbalta) Duloxetine in some ways, but in laboratory and animal studies does a better job at balancing body chemistry. New compound is 10 times better than Duloxetine at inhibiting the re-uptake of norepinephine and comes close to the perfectly balanced antidepressant with fewer side effects, such as concerns with constipation and hypotension. Though clinical studies are essential to substantiate the claims its a good achievement...

Ref : http://pubs.acs.org/doi/abs/10.1021/jm900847b

Celastrol Inhibiting Hsp90 Chaperoning - a new way to treat cancer?

Celastrol, derived from trees and shrubs called celastracaea,  (Thunder of God Vine) has been used for centuries in China to treat symptoms such as fever, chills, joint pain and inflammation.Celastrol has been shown to possess antioxidant, anti-inflammatory activities. The same compound has been tried for Alzheimer's disease and anticancer activity  also.

Now Dr. Ahmed Chadli, has come up with an interesting findings i.e., Celastrol may play a role in cancer treatment by inactivating a protein required for cancer growth.  Protein, P23, is one of many proteins helping the heat shock protein 90. Dr. Chadli claims that,  "scientists are just beginning to realize the potential of controlling inflammation-related diseases, including cancer, by inhibiting HSP90".

As per  claim by Dr. Chadli, cancer cells need HSP90 more than normal cells because cancer cells have thousands of mutations. They need chaperones all the time to keep their mutated proteins active. By taking heat shock proteins away from cells, the stabilization is taken away and cell death occurs. 

Most HSP90 inhibitors lack selectivity, disabling the functions of all proteins activated by HSP90 rather than only the ones implicated in a specific tumor and proteins vary from one tumor to another. Dr. Chadli and colleagues at the Mayo Clinic believe celastrol holds the key to specificity, targeting the HSP90-activated protein required for folding steroid receptors.

Celastrol inhibits the Hsp90 chaperoning machinery by inactivating the co-chaperone p23, resulting in a more selective destabilization of steroid receptors compared with kinase clients. Both in vitro and in vivo results demonstrate that celastrol disrupts p23 function by altering its three-dimensional structure, leading to rapid formation of amyloid-like fibrils. This study reveals a unique inhibition mechanism of p23 by a small molecule that could be exploited in the dissection of protein fibrillization processes as well as in the therapeutics of steroid receptor-dependent diseases....

Ref : http://www.jbc.org/content/285/6/4224.abstract

Metformin helps dieting teens to lose weight....

We know that Metformin  (see structure), is a  biguanide hypoglycemic  agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin's pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. In my earlier blogs, I have covered the recent (findings)  updates on metformin.

Now researchers  lead by Dr. Darrell Wilson (from Division of Pediatric Endocrinology and Diabetes, Stanford University)  have found that metformin appears to help overweight teenagers lose weight when combined with a program designed to help them change their lifestyle habits.

As per the claim by the authors though metformin hydrochloride is  used as a primary or adjunctive treatment in obese  nondiabetic adolescents there are limited short-term data to support this therapy  and also it is unclear whether any observed effects of metformin on body mass index. Therefore  the researchers conducted a 48-week randomized, double-blind, placebo-controlled trial of extended-release (XR) metformin therapy in nondiabetic obese adolescents  followed by a 48-week monitoring period after completion of treatment.

Researchers found that the addition of metformin to a lifestyle change intervention for a period of 12 months resulted in a significant improvement of BMI regardless of baseline fasting insulin levels, that persisted for 12 to 24 weeks after cessation of drug treatment. The mean (SE) reduction in BMI of –1.1 (0.5) at 1 year was comparable with that observed in other randomized controlled trials of metformin treatment in obese adolescents, although these randomized controlled trials involved shorter treatment duration (about 6 months), targeted obese children with additional diabetes risks, and had smaller sample sizes.

The mechanisms of action for these effects have not fully been elucidated but may involve beneficial effects on carbohydrate and lipid metabolism, mediated through adenosine monophosphate kinase.

Researchers conclude that  "metformin  in combination with lifestyle modification, had a small but statistically significant effect to reduce BMI in obese adolescents; this effect waned within 12 to 24 weeks of discontinuing metformin treatment". These results indicate that metformin may have an important role in the treatment of adolescent obesity. Longer-term studies will be needed to define the effects of metformin treatment on obesity-related disease risk in this population....

Ref : http://archpedi.ama-assn.org/cgi/content/full/164/2/116?home