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Novartis First-Generation Lung Cancer Drug Tweaked To Reduce Potential Side Effects
Sponge molecules isolated and synthesized for drug trials
By scouring the oceans for disease-fighting molecules, researchers have identified two new anticancer compounds. Isolated from a sea sponge, the compounds represent a new class of the natural products called polyketides, many of which have biological activity. Because it’s not possible to extract sufficient amounts of the molecules from the sponges, the researchers also devised chemical syntheses that allowed them to make enough material to initiate clinical trials on one of the substances,
Cancer Fighters From The Sea
Natural Products: Sponge molecules isolated and synthesized for drug trials.
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BENAZEPRIL SYNTHESIS
CAS NO AS HCl SALT
| 86541-75-5 |
The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride
WO 2003092698 A1
Pilot Plant PAT Approach for the Diastereoselective Diimide Reduction of Artemisinic Acid
Pilot Plant PAT Approach for the Diastereoselective Diimide Reduction of Artemisinic Acid
In this study, an attractive route for the diastereoselective synthesis of dihydroartemisinic acid (DHAA) starting from artemisinic acid (AA) is presented. Diimide was used as a reducing agent, which was generated by two different methods: (1) by the reaction of hydrazine monohydrate and hydrogen peroxide and (2) by the reaction of hydrazine monohydrate and oxygen. Both methods were found to be suitable for the diimide reduction of AA showing full conversion and a high diastereoselectivity. Due to advantages in the crystallization step of DHAA, the second option for generation of diimide was chosen for the pilot plant scale-up. The reaction and the crystallization process development as well as the batch production in the pilot plant were monitored and controlled using dispersive Raman spectroscopy as PAT tool. Three DHAA batches in kilogram scale were successfully produced by the reaction of artemisininic acid, hydrazine monohydrate, and a gas mixture of nitrogen and oxygen (containing 5% v/v oxygen) in 2-propanol at 40 °C. Excellent yields of >90% (including the crystallization, isolation, and drying step) as well as high diastereoselectivities (≥97:3) of the products were achieved by the elaborated pilot plant manufacturing processes.
Novartis’ Serelaxin Gets FDA Breakthrough Designation
Recognition by the US Food and Drug Administration (FDA) that RLX030 has the potential to address a serious unmet medical need
If approved, RLX030 has the potential to be the first treatment breakthrough for Acute Heart Failure patients in 20 years
RLX030 is the second Breakthrough Therapy designation by the FDA for Novartis investigational treatments, following LDK378
Basel, June 21, 2013 – Novartis announced today that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation status to RLX030 (serelaxin), an investigational treatment for patients with acute heart failure (AHF). The FDA has concluded that RLX030 qualifies for a Breakthrough Therapy designation after considering the available clinical evidence which supports a substantial improvement over currently available therapies for AHF[3], a life-threatening illness…………….
http://www.pharmalive.com/novartis-serelaxin-gets-fda-breakthrough-designation
Serelaxin (RLX030) is an investigational drug targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time , such as increased blood output of the heart and blood flow in the kidney.
Serelaxin is currently undergoing clinical trials in patients with acute heart failure, and is being developed by Novartis.
structure
L-Serine, L-α-aspartyl-L-seryl-L-tryptophyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-valylL-isoleucyl-L-lysyl-L-leucyl-L-cysteinylglycyl-L-arginyl-L-α-glutamyl-L-leucyl-L-valyl-L- arginyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-alanyl-L-isoleucyl-L-cysteinylglycyl-L- methionyl-L-seryl-L-threonyl-L-tryptophyl-, cyclic (11→11′),(23→24′)-bis(disulfide) with 5-oxo-L-prolyl-L-leucyl-L-tyrosyl-L-seryl-L-alanyl-L-leucyl-L-alanyl-L-asparaginyl-L-lysyl-L- cysteinyl-L-cysteinyl-L-histidyl-L-valylglycyl-L-cysteinyl-L-threonyl-L-lysyl-L-arginyl-L- seryl-L-leucyl-L-alanyl-L-arginyl-L-phenylalanyl-L-cysteine cyclic (10’→15′)-disulfide
CHEMICAL NAMES
1. L-Serine, L-α-aspartyl-L-seryl-L-tryptophyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-valyl-
L-isoleucyl-L-lysyl-L-leucyl-L-cysteinylglycyl-L-arginyl-L-α-glutamyl-L-leucyl-L-valyl-L-
arginyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-alanyl-L-isoleucyl-L-cysteinylglycyl-L-
methionyl-L-seryl-L-threonyl-L-tryptophyl-, cyclic (11→11′),(23→24′)-bis(disulfide) with
5-oxo-L-prolyl-L-leucyl-L-tyrosyl-L-seryl-L-alanyl-L-leucyl-L-alanyl-L-asparaginyl-L-lysyl-L-
cysteinyl-L-cysteinyl-L-histidyl-L-valylglycyl-L-cysteinyl-L-threonyl-L-lysyl-L-arginyl-L-
seryl-L-leucyl-L-alanyl-L-arginyl-L-phenylalanyl-L-cysteine cyclic (10’→15′)-disulfide
2. Human relaxin 2 (relaxin H2)
MOLECULAR FORMULA C256H408N74O74S8
MOLECULAR WEIGHT 5.96 kDa
SPONSOR Novartis Pharma AG
CODE DESIGNATION RLX030
CAS REGISTRY NUMBER 99489-94-8
Treatment of acute heart failure
Structure
http://www.ama-assn.org/resources/doc/usan/serelaxin.pdf
- H. Spreitzer (4 March 2013). “Neue Wirkstoffe – Serelaxin”. Österreichische Apothekerzeitung (in German) (5/2013): 36.
- Dirk Einecke (23 November 2012). “Schwangerschaftshormon gegen Herzschwäche” [Pregnancy hormone against heart failure]. ÄrzteZeitung.
- Conrad KP (August 2011). “Maternal vasodilation in pregnancy: the emerging role of relaxin”. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301 (2): R267–75. doi:10.1152/ajpregu.00156.2011. PMC 3154715. PMID 21613576.
- Teerlink, John R; Cotter, Gad; Davison, Beth A; Felker, G Michael; Filippatos, Gerasimos; Greenberg, Barry H; Ponikowski, Piotr; Unemori, Elaine; Voors, Adriaan A; Adams, Kirkwood F; Dorobantu, Maria I; Grinfeld, Liliana R; Jondeau, Guillaume; Marmor, Alon; Masip, Josep; Pang, Peter S; Werdan, Karl; Teichman, Sam L; Trapani, Angelo; Bush, Christopher A; Saini, Rajnish; Schumacher, Christoph; Severin, Thomas M; Metra, Marco (1 November 2012). “Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial”. The Lancet.doi:10.1016/S0140-6736(12)61855-8.
PLASTIC SURGERY-Breast Lift Surgery-mastopexy
Breast lift, or mastopexy, surgery raises and firms the breasts by removing excess skin and tightening the surrounding tissue to reshape and support the new breast contour.
Breast lift procedure steps
What happens during breast lift surgery? Your mastopexy surgery can be achieved through a variety of incision patterns and techniques. The appropriate technique for you will be determined based on:
- Breast size and shape
- The size and position of your areolas
- The degree of breast sagging
- Skin quality and elasticity as well as the amount of extra skin
Step 1 – Anesthesia
Medications are administered for your comfort during breast lift surgery. The choices include intravenous sedation and general anesthesia. Your doctor will recommend the best choice for you.
Step 2 – The incision
There are three common incision patterns:
Around the areola, . note-pics deleted
Around the areola and vertically down from the areola to the breast crease
Around the areola, vertically down from the breast crease and horizontally along the breast crease
Step 3 – Reshaping your breasts
After your doctor makes the incisions:
- The underlying breast tissue is lifted and reshaped to improve breast contour and firmness.
- The nipple and areola are repositioned to a natural, more youthful height.
- If necessary, enlarged areolas are reduced by excising skin at the perimeter.
- Excess breast skin is removed to compensate for a loss of elasticity.
Step 4 – Closing the incisions
After your breasts are reshaped and excess skin is removed, the remaining skin is tightened as the incisions are closed.
Some incision lines resulting from breast lifts are concealed in the natural breast contours; however, others are visible on the breast surface. Incision lines are permanent, but in most cases will fade and significantly improve over time.
Sutures are layered deep within the breast tissue to create and support the newly shaped breasts. Sutures, skin adhesives and/or surgical tape may be used to close the skin.
Step 5 – See the results
The results of your breast lift surgery are immediately visible. Over time, post-surgical swelling will resolve and incision lines will fade.
Satisfaction with your new image should continue to grow as you recover and realize the fulfillment of your goal for breasts which have been restored to a more youthful and uplifted position.
Pfizer, GSK form productivity pact with Singapore’s A*Star
Pfizer, GlaxoSmithKline and engineering giant Siemens have signed on as founding members of a new consortium set up by Singapore’s Agency for Science, Technology and Research (A*Star) to address challenges such as costs, regulatory compliance and processes to bring drugs from trials to markets.
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The Agency for Science, Technology and Research (Abbreviation: A*STAR; Chinese: 新加坡科技研究局) is a statutory board under the Ministry of Trade and Industry of Singapore. The Agency was established in 1991 to foster scientific research and talent for a knowledge-based Singapore.
Established in 1991 as the former National Science and Technology Board (NSTB), A*STAR was established with the primary mission to raise the level of science and technology in Singapore.[1]
Leadership
The current chairman of A*STAR is Mr. Lim Chuan Poh. He was formerly the Permanent Secretary (Education) and the Chief of Defence Force. Mr Lim took over the reins of A*STAR from Mr. Philip Yeo, who later became Chairman of SPRING Singapore, on 1 April 2007.[2]
The scientific leadership includes Tan Chorh Chuan, George Radda, Sydney Brenner, David Lane, Charles Zukoski and used to include Prof Low Teck Seng. Prof Low Teck Seng left A*Star on 19 July 2012 to join the National Research Foundation of the Prime Minister’s Office.
A*STAR Entities
The agency is made up of:
- The Biomedical Research Council (BMRC) – Oversees public sector research activities in the biomedical sciences
- The Science and Engineering Research Council (SERC) – Oversees public sector research activities in the physical sciences & engineering
- The A*STAR Joint Council (A*JC) – Promotes and supports interdisciplinary collaborations between biomedical sciences, and physical sciences & engineering
- The A*STAR Graduate Academy (A*GA) – Administers science scholarships and other manpower development programs
- Exploit Technologies Pte Ltd (ETPL) – Manages the intellectual property created by research institutes in Singapore, and facilitates technology transfer to industry
- The Corporate Group – Supports the rest of the organisation with finance, human resources, legal and other services
The agency oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and six consortia & centre, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.
A*STAR supports Singapore’s key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.
Research Institutes & Units
Biomedical Research Council
The Biomedical Research Council (BMRC) oversees 7 research institutes and several other research units that focus on both basic as well as translational and clinical research to support the key industry clusters in Biomedical Sciences, pharmaceuticals, medical technology, biotechnology and healthcare services.
Having established a strong foundation in basic biomedical research capabilities, there is now an added focus on translating new knowledge and technologies created at the “benches” into new clinical applications for diagnosis and treatment that can one day be delivered at the “bedsides” of our hospitals and disease centres.
The research institutes and units under BMRC are:
- Bioinformatics Institute (BII)
- Bioprocessing Technology Institute (BTI)
- Experimental Therapeutics Centre (ETC)
- Genome Institute of Singapore (GIS)
- Institute of Bioengineering and Nanotechnology (IBN)
- Institute of Medical Biology (IMB)
- Institute of Molecular and Cell Biology (IMCB)
- Neuroscience Research Partnership (NRP)
- Singapore Bioimaging Consortium (SBIC)
- Singapore Immunology Network (SIgN)
- Singapore Institute for Clinical Sciences (SICS)
- Singapore Stem Cell Consortium (SSCC)
- A*STAR-NUS Clinical Imaging Research Centre (CIRC)
The BMRC Research Institutes focus on building up core biomedical capabilities in the areas of bioprocessing; chemical synthesis; genomics and proteomics; molecular and cell biology; bioengineering and nanotechnology and computational biology. In addition, the Institute of Medical Biology (IMB) and Singapore Institute for Clinical Sciences (SICS) focus on translational and clinical research.
Science and Engineering Council
A*STAR’s Science and Engineering Research Council (SERC) promotes public sector research and development in the physical sciences & engineering.
SERC manages seven research institutes and several state-of-the art centres and facilities with core competencies in a wide range of fields including communications, data storage, materials, chemicals, computational sciences, microelectronics, advanced manufacturing and metrology to tackle global technological challenges and create future industries from its headquarters at Fusionopolis, Singapore’s iconic hub for science and technology research.
The research institutes and units under SERC are:
- Data Storage Institute (DSI)
- Institute of Chemical Engineering and Sciences (ICES)
- Institute of High Performance Computing (IHPC)
- Institute of Infocomm Research (I2R)
- Institute of Materials Research and Engineering (IMRE)
- Institute of Microelectronics (IME)
- Singapore Institute of Manufacturing Technology (SIMTech)
- National Metrology Centre (NMC)
The seamless integration of the research institutes is key to addressing industry needs, which may span multiple disciplines. To this end, SERC’s broad range of capabilities are in a unique position to develop new technologies in areas such as automotives, aerospace, energy, electronic healthcare and medical technology, nanotechnology, photonics, sensors and sensor networks.
In July 2012, it was announced that A*STAR collaborates with Chinese language internet search provider Baidu to open a joint laboratory, called the Baidu-I2R Research Centre (BIRC), which aims to develop language processing technologies.[3]
Scholarships
Each year, the Agency gives out a number of scholarships and awards to young and aspiring scientists. These awards are meant to help Singapore achieve its goal of becoming a research hub by nurturing home-grown PhDs to serve both in the public sector and in industry. In 2008, a total of 101 scholarships were awarded to Bachelor of Science and PhD students who were to embark on their studies in overseas universities.[4] The administration of these awards are governed by the A*Star Graduate Academy, some of which are listed below:
- National Science Scholarship (BS)
- National Science Scholarship (PhD)
- A*Star Graduate Scholarship
- Singapore International Graduate Award (SINGA)
- Singapore International Pre-Graduate Award (SIPGA)
- A*Star Pre-Graduate Award
- A*Star International Fellowship
References
www.a-star.edu.sg
- “Agency for Science, Technology and Research (A*STAR)”. Ministry of Trade and Industry. Retrieved 30 March 2011.
- Chang Ai-Lien, “S’pore’s science salesman turns sights on SMEs”, The Straits Times, 21 October 2006
- “Baidu, A*STAR open joint laboratory”. Channel News Asia. Retrieved 26 July 2012.
- More Than 300 Young People Receive A*STAR Scholarships And Awards At A*STAR Scholarship Award Ceremony 2008, 25 July 08
Supervision of Chinese-Made Drug Substances by Philippe André
Why source drug substances from China?
Large markets, economies of scale and cheaper labor;An industrial ecosystem supplying raw materials and equipment;Developed infrastructure and industry friendly policies;About 5,000 manufacturers;
Thousands of chemists and students across China looking for novel synthesis routes for generic drug substances and intermediates.
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http://www.allfordrugs.com/2013/06/21/supervision-of-chinese-made-drug-substances-by-philippe-andre/
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 