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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Marijuana shows potential in treating autoimmune disease
A team of University of South Carolina researchers led by Mitzi Nagarkatti, Prakash Nagarkatti and Xiaoming Yang have discovered a novel pathway through which marijuana can suppress the body’s immune functions. Their research has been published online in the Journal of Biological Chemistry.
Marijuana is the most frequently used illicit drug in the United States, but as more states legalize the drug for medical and even recreational purposes, research studies like this one are discovering new and innovative potential health applications for the federal Schedule I drug.
Marijuana is now regularly and successfully used to alleviate the nausea and vomiting many cancer patients experience as side effects to chemotherapy, combat the wasting syndrome that causes some AIDS patients to lose significant amounts of weight and muscle mass and ease chronic pain that is unresponsive to opioids, among other applications.
The university study has uncovered yet another potential application for
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Neuron tells stem cells to grow new neurons
In this artist’s representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells. Credit: O’Reilly Science Art
Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.
Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.
In a study with mice, his team found a previously unknown population of neurons within…
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Activating the immune system could treat obesity and diabetes
Obesity is a worldwide epidemic that is causing alarming rates of diabetes and cardiovascular disease, but currently there is a lack of effective drug treatments. Two unrelated studies published by Cell Press June 5th in the journal Cell reveal an important role for immune pathways in activating good types body fat, called brown and beige fat, which burn stored calories, reduce weight, and improve metabolic health. The findings could pave the way for much-needed treatments for obesity and related metabolic diseases.
“The idea that metabolic health can be improved by activation of immune cells in fat is pretty amazing,” says senior study author Bruce Spiegelman of the Dana-Farber Cancer Institute and Harvard Medical School. “This research reveals an exciting new class of potential treatments that could one day be used for obesity-related disorders.”
Human infants have large amounts of heat-generating brown fat to protect them from extreme cold, and…
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Ancient chemical bond may aid cancer therapy
A chemical bond discovered by Vanderbilt University scientists that is essential for animal life and which hastened the “dawn of the animal kingdom” could lead to new therapies for cancer and other diseases.
The report, published online today by the Proceedings of the National Academy of Sciences(PNAS), was co-authored by 83 participants in the “Aspirnaut” K-20 STEM pipeline program for diversity. Six were middle school students when the study was conducted, 42 were high school students, 30 were college undergraduates and five were graduate students.
Because many of the high school students grew up in poverty in rural communities, “they’re invisible. They’re an untapped talent pool,” said Billy Hudson, Ph.D., who founded the Aspirnaut program with his wife and co-senior author Julie Hudson, M.D. “Aspirnaut connects the ‘Forgotten Student’ to STEM opportunities.”
The study demonstrates that the sulfilimine bond, which Hudson’s group discovered in 2009, is part…
View original post 228 more words
GSK launches huge Phase III trial for heart drug losmapimod (GW856553)
losmapimod
Losmapimod is a p38 mitogen-activated protein kinase inhibitor.
Smithkline Beecham Corporation
6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide
cas 585543-15-3
Synonym: Losmapimod; GW856553; GW-856553; GW 856553)
IUPAC/Chemical name:
6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide
GlaxoSmithKline has begun a Phase III study cardiovascular outcomes study of its investigational compound losmapimod in patients with acute coronary syndrome.
The trial will assess whether losmapimod can reduce the risk of a subsequent cardiac event when administered orally twice a day for three months immediately after presentation with an ACS, such as heart attack. GSK says that some 25,500 patients will be enrolled over the study period across 39 countries.
Read more at: http://www.pharmatimes.com/Article/14-06-06/GSK_launches_huge_Phase_III_trial_for_heart_drug_losmapimod.aspx#ixzz33vFHAK14
Losmapimod, also know as GW856553 or GW856553X, is a drug developed by GlaxoSmithKline which acts as a selective inhibitor of the enzyme family known as p38 mitogen-activated protein kinases. p38 mitogen-activated protein kinases are mediators of inflammation. A Phase II human clinical trial for the treatment of COPD (chronic obstructive pulmonary disease) is underway. Inhibiting these enzymes has been shown to produce antidepressant and antipsychotic effects in animal studies, with the mechanism thought to involve increased neurogenesis probably related to BDNF release. Losmapimod has completed Phase II human clinical trials for the treatment of depression although its safety and efficacy have yet to be proven in further trials. Losmapimod is also being studied for cardiovascular disease. A Phase II trial to study its effects in myocardial infarction (heart attack) is ongoing.
Losmapimod (GW856553X) is a drug developed by GlaxoSmithKline which acts as a selective inhibitor of the enzyme family known as p38 mitogen-activated protein kinases.[1]
p38 mitogen-activated protein kinases are mediators of inflammation. A Phase II human clinical trial for the treatment of COPD(chronic obstructive pulmonary disease)[2] is underway. Inhibiting these enzymes has been shown to produce antidepressant andantipsychotic effects in animal studies, with the mechanism thought to involve increased neurogenesis[3] probably related to BDNFrelease. Losmapimod has completed Phase II human clinical trials for the treatment of depression although its safety and efficacy have yet to be proven in further trials.[4]
Losmapimod is also being studied for cardiovascular disease.[5] A Phase II trial to study its effects in myocardial infarction (heart attack) is ongoing.[6]
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http://www.google.com/patents/US8252818
| Example 36 6-(5- Cyclopropylcarbamoyl- 3-fluoro-2-methyl- phenyl)-N-(2,2- dimethylpropyl)- nicotinamide |
 |
6-Chloro-N-(2,2- dimethylpropyl))nicotin- amide (Intermediate 24) | 384 | 3.01 |
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https://www.google.com/patents/US7514456
General Method A
6-Bromonicotinic acid (100 mg, 0.5 mmol) was heated at 95° C. in thionyl chloride (0.63 ml) for 2 hours. The excess thionyl chloride was evaporated under vacuum and the residue dissolved in DCM (2 ml). To this solution, amine (0.5 mmol) and sodium carbonate (100 mg) were added and the reaction was stirred at room temperature for 2 hours. The reaction was filtered and the residue washed with DCM. The combined filtrate and washings were reduced to dryness to give the desired 6-chloronicotinamide.
| Retention time | |||
| Compound | Amine | MH+ | (minutes) |
| Intermediate 22: 6-Chloro-N-(3- | 3-methylbutylamine | 227 | 2.92 |
| methylbutyl)nicotinamide | |||
| Intermediate 23: 6-Chloro-N-(1- | 1-cyclopropylethylamine | 225 | 2.65 |
| cyclopropylethyl)nicotinamide | |||
| Intermediate 24: 6-Chloro-N-(2,2- | 2,2-dimethylpropylamine | 227 | 2.82 |
| dimethylpropyl))nicotinamide | |||
| Intermediate 25: 6-Chloro-N-(2,2- | 2,2- | 225 | 2.67 |
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Nicotinamide derivatives useful as P38 inhibitors
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8-3-2011
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Use of a p38 Kinase Inhibitor for Treating Psychiatric Disorders
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11-24-2010
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3-Aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
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8-27-2010
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NICOTINAMIDE DERIVATES USEFUL AS P38 INHIBITORS
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5-5-2010
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Nicotinamide Derivatives Useful as p38 Inhibitors
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4-8-2009
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Nicotinamide Derivatives Useful as p38 Inhibitors
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10-25-2006
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Nicotinamide derivatives useful as p38 inhibitors.
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References
- Aston N, Bamborough P, Buckton J, Edwards C, Holmes D, Jones K, Patel V, Smee P, Somers D, Vitulli G, Walker A. p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression.Journal of Medicinal Chemistry 2009, 52(20), 6257. doi:10.1021/jm9004779
- Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Subjects With Chronic Obstructive Pulmonary Disease (COPD)
- Noh JS, Kang HJ, Kim YE, Sohn S, Chung YK, Kim SU, Gwag BJ. Haloperidol-Induced Neuronal Apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase. Journal of Neurochemistry 2000, 75(6), 2327. PMID 11080184 doi:10.1046/j.1471-4159.2000.0752327.x
- A Study of GW856553X For the Treatment of Depression
- Cheriyan et al., Circulation 2011, 123(5), 515-523. Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia doi:10.1161/CIRCULATIONAHA.110.971986
- A Study to Evaluate the Safety of 12 Weeks of Dosing With GW856553 and Its Effects on Inflammatory Markers, Infarct Size, and Cardiac Function in Subjects With Myocardial Infarction Without ST-segment Elevation (Solstice)
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more References |
1: Yang S, Beerahee M. Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials. Eur J Clin Pharmacol. 2013 Jun;69(6):1261-7. doi: 10.1007/s00228-012-1469-1. Epub 2013 Jan 17. PubMed PMID: 23325437.
2: Yang S, Lukey P, Beerahee M, Hoke F. Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases. Clin Pharmacokinet. 2013 Mar;52(3):187-98. doi: 10.1007/s40262-012-0025-6. PubMed PMID: 23254770.
3: Dewenter M, Vettel C, El-Armouche A. [Losmapimod: a novel drug against cardiovascular diseases?]. Dtsch Med Wochenschr. 2013 Jan;138(1-2):39-42. doi: 10.1055/s-0032-1327368. Epub 2012 Dec 18. Review. German. PubMed PMID: 23250695.
4: Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2013 Jul;17(6):844-57. doi: 10.1002/j.1532-2149.2012.00256.x. Epub 2012 Dec 14. PubMed PMID: 23239139.
5: Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063. PubMed PMID: 23215699; PubMed Central PMCID: PMC3703232.
6: Melloni C, Sprecher DL, Sarov-Blat L, Patel MR, Heitner JF, Hamm CW, Aylward P, Tanguay JF, DeWinter RJ, Marber MS, Lerman A, Hasselblad V, Granger CB, Newby LK. The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale. Am Heart J. 2012 Nov;164(5):646-653.e3. doi: 10.1016/j.ahj.2012.07.030. Epub 2012 Oct 16. PubMed PMID: 23137494.
7: Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA, Tawakol A, Gleeson FV, Lepore JJ, Davis B, Willette RN, Wilkinson IB, Sprecher DL, Cheriyan J. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging. 2012 Sep;5(9):911-22. doi: 10.1016/j.jcmg.2012.02.016. PubMed PMID: 22974804.
8: Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H, Barnes NC, Tal-Singer R; Losmapimod Study Investigators. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 2012 Mar;52(3):416-24. doi: 10.1177/0091270010397050. Epub 2011 Nov 16. PubMed PMID: 22090363.
9: Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24. PubMed PMID: 21262998.
10: Welchman R. Advances and Progress in Drug Design – SMi’s ninth annual meeting. IDrugs. 2010 Apr;13(4):239-42. PubMed PMID: 20373252.
11: Willette RN, Eybye ME, Olzinski AR, Behm DJ, Aiyar N, Maniscalco K, Bentley RG, Coatney RW, Zhao S, Westfall TD, Doe CP. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther. 2009 Sep;330(3):964-70. doi: 10.1124/jpet.109.154443. Epub 2009 Jun 25. PubMed PMID: 19556450.
GSK Announces Phase III Cardiovascular Outcomes Study with Losmapimod in Patients with Acute Coronary Syndrome
GlaxoSmithKline plc Thursday 5 June 2014, London UK (LSE/NYSE: GSK) today announced the start of a pivotal phase III study, LATITUDE-TIMI 60, to evaluate the effects of losmapimod in patients presenting with acute coronary syndrome. The global, phase III study will assess whether losmapimod can reduce the risk of a subsequent cardiac event when administered…
Fasting for three days can regenerate entire immune system, study finds
Fasting for as little as three days can regenerate the entire immune system, even in the elderly, scientists have found in a breakthrough described as “remarkable”.
Although fasting diets have been criticised by nutritionists for being unhealthy, new research suggests starving the body kick-starts stem cells into producing new white blood cells, which fight off infection.
Scientists at the University of Southern California say the discovery could be particularly beneficial for people suffering from damaged immune systems, such as cancer patients on chemotherapy.
It could also help the elderly whose immune system becomes less effective as they age, making it harder for them to fight off even common diseases.
The researchers say fasting “flips a regenerative switch” which prompts stem cells to create brand new white blood cells, essentially regenerating the entire immune system.
“It gives the ‘OK’ for stem cells to go ahead and begin proliferating and rebuild the…
View original post 575 more words
Tie up with Emcure…..Roche to launch cheaper cancer drugs in India
Reuters | Updated On: June 06, 2012 12:36 (IST)
Mumbai:
Swiss drugmaker Roche Holding AG plans to offer cut-price versions of two blockbuster cancer drugs for the Indian market soon, a company spokesman said on Friday, days after New Delhi moved to slash the price of a rival cancer treatment.
India stripped German’s Bayer AG of its exclusive rights to Nexavar earlier this month and licensed a local drugs company to produce a cheap, generic version, on the grounds that poor Indians could not otherwise afford the life-saving drug.
Roche, the world’s biggest maker of cancer drugs, said it would offer “significantly” cheaper, locally branded versions of its two cancer drugs, Herceptin and MabThera, by early next year, under an alliance with India’s Emcure Pharmaceuticals Ltd.
http://profit.ndtv.com/news/corporates/article-roche-to-launch-cheaper-cancer-drugs-in-india-300344
Russian scientists create cancer cure that doubles life span
Scientists in the Russian city of Novosibirsk have created a vaccine that can double a cancer patient’s life expectancy. The drug has already been tested clinically and may soon appear in stores.
When given to patients suffering from the third and fourth stage of colorectal, breast and prostate cancer, the treatment can significantly prolong their life span, says Vladimir Kozlov, the head of the Clinical Immunology Institute that did the research.
The vaccine is extracted from the dendritic cells, which are immune cells producing antigen material. The patient’s dendritic cells are then altered with the tumor cell culture and injected into the organizm, triggering an immune response, which means they attack cancer.
The treatment is now available to people after a cancer surgery, although scientists envisage the drug would be able to cure cancer in the early stages.
New therapy wipes out cervical cancer in two women
Aricca Wallace knew she was nearly out of time. For more than three years, she had suffered cramping and irregular bleeding, which her doctor thought was a side effect of her birth control implant, known as an intrauterine device, or IUD. Her annual Pap smears were always normal, so no one suspected cancer.
Except it was cancer, and by the time the 34-year-old mother of two had the IUD removed and was finally diagnosed, her tumors had reached stage three and the disease was spreading through the lymph nodes in her abdomen and chest.
“I was told by a specialist that there wasn’t any chemo that could kill it,” Wallace told AFP. “And that I’d be gone in a year.”
That was in February 2012. A few months later, Wallace’s doctor told her about an immunotherapy trial at the National Institutes of Health Clinical Center, a research hospital just outside the…
View original post 646 more words
New Drug Approvals 