#RIP Bardoxolone: Another Potential Megablockbuster Drug Fails!!

Another Potential Blockbuster Drug namely Bardoxolone ( refer this article published earlier: http://www.pharmablockbusters.info/2011/12/bardoxolone-potential-mega-blockbuster.html ) felt the axe as it failed to clear the Ph III Clinical trials due to concerns about death and "excess serious adverse events" in patients taking the first-in-class antioxidant inflammation mediator (AIM).

Bardoxolone was being developed in late-stage clinical trials by Reata Pharmaceuticals for the treatment of moderate to severe chronic kidney disease (CKD) in Type-2 Diabetes patients. The failure was a huge setback for Abbott Pharma which had paid Reata Inc. $450 million, plus milestone payments, in 2010, to license Bardoxolone for sales outside the U.S and Asia. It was to be one of the major products for the newly formed AbbVie Pharma* (split from Abbott Pharmaceuticals recently) along with arthritis blockbuster Humira (Adalimumab).

Bardoxolone was originally seen as a promising cancer dug. but in one of its cancer studies, researchers saw a big improvement in renal function among all renal cancer patients. Arrested progression of CKD or recovered kidney function was a provocative finding, and Reata pushed ahead with two Ph IIa trials for CKD in 2008, which produced positive results.

Some doctors involved in the trials believed that the trial's design had been a mistake from the outset, and that bardoxolone's potential side-effects could accelerate kidney disease.

The future seems uncertain for other AIMs (antioxidant inflammation mediators) as Bardoxolone joins the long list of Ph III failures after a promising start.

*On more information on AbbVie spinoff, visit: http://www.pmlive.com/pharma_news/abbott_completes_split_as_abbvie_debuts_on_nyse_457376

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The 3rd INDO-GERMAN Conference on Modelling Chemical and Biological (Re) Activity @ NIPER, Mohali

The 3rd Indo-German Conference on Modelling Chemical and biological (Re) Activity will be held at NIPER, S.A.S.Nagar from 26th Feb to 1st March, 2013. The 3rd edition of this conference is being held jointly by NIPER, S.A.S.Nagar and IISER, Mohali, the previous two being at Hyderabad in 2007 and Wildbad Kreuth, Germany in 2009.

The Symposium was initiated with the aim of integrating the field of pharmaceutical chemistry with various theoretical computational methods which can help solve the various problems faced in a synthetic chemistry lab. The past two meetings have been successful in identifying the future applications of theoretical methods to molecularly defined problems resulting in appropriate combinations of currently existing methods. These include quantum mechanical methods of varying sophistication as well as simpler parametrized models involving effective potentials.The current edition explores further on the same prospects and will focus even more on the aspect of graduate-level education on selected topics. Together with the poster session involving all participating graduate students this format ensures maximum educational value for all participating graduate students from the German and the Indian side.

GOALS OF THE SYMPOSIUM

To have an Indo-German meeting on interconnecting concepts in computational modeling of chemical reactivity and biological activity. Both fields have in common the challenge of working with large systems at molecular resolution as well as the goal to match existing experimental data with high accuracy. Theoretical methods are expected to provide quantitative models for the rationalization of existing data and for the prediction of the properties of new systems in pharmaceutical and catalysis research. A list of possible subtopics includes:

1. Biological Activity Catalysis
2. Drug-Receptor Interactions
3. Macromolecular Modeling
4. Molecular Dynamics
5. Non-covalent Interactions
6. Property Design
7. Reaction Mechanisms
8. Reactivity Descriptors

Aside from the question of methodological and conceptual exchange, particular emphasis will be given to the training and involvement of younger scientists and the systematic development of an exchange-based cooperative network. To this end the symposium will feature five training sessions on topics of general interest. These training sessions will be given in a workshop format requiring the active involvement of the participation of the audience. A second important element for student involvement is the poster session, which is planned for the first day of the symposium in an open-end format.

Target Audience:

Computational Chemists
Biological Chemists
Organic chemists
Medicinal Chemists
Theoretical Chemists
Bio/pharmacoinformatics Professionals
College Graduates in Chemistry, biology, etc.

IMPORTANT DATES

Last Date of registration :                         31st December, 2012

Last Date of Abstract Submission:         31st December, 2012

For Registration, CLICK HERE

Online Registration can also be done.

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Breakthrough Research: Cure for Morphine Addiction found!!

In a major breakthrough by a group of Australian scientists, a cure has been found for morphine and heroin addiction which will prove a boon for more than 12 million drug addicts worldwide.(1)

Scientists at the University of Adelaide have identified an immune receptor TLR-4 which is responsible for the drug addiction, and found a way to block this receptor without affecting pain relief.

This discovery can have wide implications as it offers the possibility of using Morphine as a pain reliever without worrying about its addictive properties. The use of morphine and other opioids is currently restricted as it can lead to some harmful effects if addicted to it. 

Morphine and other opioids are known to bind to the opioid receptors in the brain, which results in pain relief and also activation of the "Reward Pathway". This "Reward Pathway" is a result of the release of large quantities of Dopamine in the brain which is the root cause for addiction to opioids.

TLR-4 is a toll-like receptor whose role is to identify  foreign bodies,
and thus launch an immune attack against harmful pathogens.

The observation that the opioids also bind to the toll-like receptors TLR-4, eventually led the Hutchinson team to the hypothesis, that TLR-4 may act as an amplifier for award when opioids are bound to it. They performed a series of experiments pertaining to the addictive behaviour in rats, by administering a known drug (called plus naloxone- which is known to block TLR-4), and hence blocking the immune receptors. 

Rats given plus-naloxone before receiving morphine did not exhibit behaviour linked to addiction. Their brains also showed a significantly lower release of dopamine than in rats that only received morphine. Using a heat sensitivity test, the team also showed that the rodents given plus-naloxone still experienced pain relief from the morphine, despite lacking signs of addiction.

The idea that the rewarding effect of opioid drugs is potentially mediated by this receptor "flies in the face of current opinion," says Chris Bailey, a pharmacologist from the University of Bath in the UK. "People for hundreds of years have been trying to come up with an opioid analgesic which isn't rewarding," he says.
These findings are particularly interesting, he says, because it's the first time a mechanism has been identified that separates the pain relief and reward responses to opioid drugs. "It has always been seen that the analgesia and the rewarding aspects go hand in hand," he says.

 The National Institutes on Drug Abuse in U.S is further developing the drug to test in clinical trials. As a result, Clinical trials would soon be underway in the coming 2 years, Dr. Hutchinson said.

If the clinical trials were successful, opioid drugs used to relieve pain could potentially be co-formulated with the additional drugs( TLR-4 Blockers) to limit the chance of addiction.

It would also benefit the addicted patients who are admitted in hospital, and require pain relief. Addicted patients require higher doses of the drug, as they are higly tolerant to the drug, so this combination may help in lowering the doses given to the patients.

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Public Domain Databases for Medicinal Chemistry

Here's a useful overview of the public-domain medicinal chemistry databases out there. 

BindingDB (quantitative binding data to protein targets).

ChEMBL (wide range of med-chem data, overlaps a bit with PubChem).

PubChem (data from NIH Roadmap screen and many others).

PDB (repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids

Binding MOAD (literature-annotated PDB data).

ChemSpider (26 million compounds from hundreds of data sources).

DrugBank (data on 6700 known drugs).

GRAC and IUPHAR-DB (data on GPCRs, ion channels, and nuclear receptors, and ligands for all of these).

PDBbind (more annotated PDB data).

PDSP Ki (data from UNC's psychoactive drug screening program)

SuperTarget (target-compound interaction database).

Therapeutic Targets Database(database of known and possible drug targets).

ZINC (21 million commercially available compounds, organized by class, downloadable in various formats).

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Naming the Antibiotics: Some Intriguing Facts

An entertaining and brief but fully documented review of the methods by which discoverers of antibiotics have chosen names for them is given by D. Perlman of the School of Pharmacy, University of Wisconsin. 

Antibiotics named after Organisms: 

Some of the best known, and a total of about 500, have names derived from the organisms producing them, either that of the genus (penicillin, streptomycin, cephalosporins) or of the species (griseofulvin from Penicillium griseofulvum). A few, such as staphylomycin and gramicidin, denote not the source but the organisms susceptible to them.

Antibiotics named after Places:

These antibiotics are named after the geographical sources of the soil where the producing organism was cultivated.

Pimaricin, a useful antifungal antibiotic was named after Pietermaritzburg, near which the soil yielding Streptomyces natalensis was collected.

Nystatin, is the only antibiotic named after the institution in which it was isolated, the laboratories of the New York State Board of Health.

Antibiotics named after people:

1Bacitracin-- Margaret Tracy being the child with a compound fracture from whose wound the producing Bacillus was isolated, where its growth was apparently contributing to overcoming septic infection.

2Helenine, an antibiotic of no clinical value but having an interesting action on some virus infections in mice, was so named by the late R. E. Shope after his wife Helen, because he found the mould producing the antibiotic growing on the cover of a photograph of her which he was carrying while serving in the war in the Pacific.

3saramycetin (a sulphur-containing peptide with systemic antifungal activity) was named  after a mother-in-law.

Antibiotics with Peculiar Names

Reference: BRITISH MEDICAL JOURNAL, 759, 28 SEPTEMBER 1974.

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Vaccine for Brain Tumor: A New Height in Personalized Medicine

Developing a Vaccine produced from a patient's one's own tissues has definitely taken Pharmacogenomics-popularly known as "Personalized medicine" to a new height in the present scenario.

The concept of Pharmacogenomics deals with the genetic variation among the masses, and using the genetic data to select the right drugs to treat disease in a given patient. Although at a primary level, this can help the doctors in avoiding pointless treatments and reducing adverse drug reactions in the concerned patients.

Using a patient's own tissues for developing a Vaccine, is in itself a novel strategy employed by Valley Hospital in Ridgewood, N.J, wherein they are offering patients with newly diagnosed glioblastoma multiforme (GBM) (brain tumor) the opportunity to take part in the clinical trials.

The phase II trial, headed by principal investigator and researcher Anthony D'Ambrosio, M.D., director of Valley's neuro-oncology disease management team, is designed to evaluate safety, survival and immune response in patients treated with a heat shock protein peptide-complex vaccine (HSPPC-96) derived from each patient's specific tumor cells.

"Heat shock proteins are believed to play an essential role in helping the immune system to recognize and eradicate diseased cells," said D'Ambrosio.

The Glioblastoma Vaccine study is sponsored by the University of California, San Francisco, and is currently available in limited locations across the country. The study is currently searching for participants who are newly diagnosed, over age 18 and whose tumors have not been excised.

These trials indicate a new era in healthcare with the advent of personalized medicines, for the common good of humanity.

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Free SciFinder access For Unemployed

Are you currently unemployed and wish you still had access to SciFinder to help you find new employment or to stay current in your research area? If you had access to SciFinder and lost your job this year, CAS now offers complimentary SciFinder access under a special program for free. 


Apply Here

SciFinder is a research discovery tool that allows college students and faculty to access a wide diversity of research from many scientific disciplines, including biomedical sciences, chemistry, engineering, materials science, agricultural science, and more!  

SciFinder gives an instant access to the world's largest curated collection of information on disclosed chemistry and related research produced by CAS.

It includes:  References from more than 10,000 currently published journals and patents from more than 62 patent authorities.   Important scientific discoveries from the present to the mid-1800s.  The latest scientific breakthroughs almost as soon as they are published with references added daily and some patent information as recent as 2 days ago. The world's largest collection of organic and inorganic substance information.  

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International Symposium on Drug Metabolism & Pharmacokinetics @NIPER, Mohali

NIPER S.A.S. and Bristol-Myers Squibb is organizing 4th International Symposium on  Drug Metabolism  & Pharmacokinetics (DMPK) , at NIPER S.A.S. Nagar (Mohali), Punjab, India. This conference will be useful for scientific community working in the field of Drug Metabolism  & Pharmacokinetics.

Objectives of the Symposium

Provide a better understanding of the role that drug metabolism, drug transporters, pharmacokinetics, and pharmacodynamics play in the drug discovery development process.

Evaluate new and current techniques and models associated with drug metabolism and drug transporters, as well as development of pharmacokinetic-pharmacodynamic models.

Gain insights into the issues encountered during the drug discovery process and the interface between discovery and clinical development.

Identify processes for reducing the attrition of drug candidates through a better understanding of metabolism and in vitro and in vivo correlations

This is primarily a lecture-based symposium intended for students and scientists from industry, academia, health-based government organizations, and healthcare professionals with a background in chemistry, biology, or the pharmaceutical sciences, with some experience in the principles and techniques of drug metabolism and pharmacokinetics.  The symposium is also intended for experienced researchers in these areas who wish to broaden or supplement their area of expertise, as well as contribute to the discussion topics.

Important Dates:

Receipt of Abstract: 20^th Jan. 2012

Intimation of acceptance : 20^th Jan. 2012

Receipt of Reg. Fee :20^th  Jan. 2012

Dates of symposium : 16,17,18 and19^th Feb. 2012

Contact Details:

Dr. Abhay Sangamwar (Coordinator)
DMPK Symposium
Department of Pharmacoinformatics
National Institute of Pharmaceutical Education and Research 
(NIPER), Sector 67, S.A.S. Nagar (Mohali) - 160 062
Punjab, India
Phone:+91-172-2214682-87 Extn. 2211 (office)
Fax:+91-172-2214692
e-mail: dmpk2012@niper.ac.in

Register Here 

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Avalanche'12, The National level Pharma Carnival on 3-4 Feb,2012

Event Name: AVALANCHE’12
Event type: A National Level Pharma Carnival
Organizer: Ramanbhai Patel College of Pharmacy
Location: Education Campus Changa, Anand,Gujarat.


Important Dates for Avalanche'12


Event dates: February 3-4, 2012
Last date for registration: Jan 25, 2012
Eligibility: Open to all  Pharmacy students of India(D.Pharm, B.Pharm, M.Pharm)


AVALANCHE'12
The much awaited national level Pharma Carnival, ‘Avalanche’ is back in 2012 and is all set to create a nation-wide sensation as it has been with the last two editions of Avalanche. Avalanche'12 has been made all the more exciting with lot of innovative ideas and additions that may provide a platform for all the pharma students of the country to exhibit their skills.


"Avalanche....the fury of thoughts", ever since its inception in 2007 has been one of a kind national Level Pharma carnival, which has gained much recognition among the masses due to its uniqueness and fun-filled activities. Avalanche'07 was a brainchild of the First batch of RPCP started with the objective to provide a platform exclusively for Pharma Students, in synchronous to the technical Festivals commonly observed in Engineering Colleges.


The second TechFest - Avalanche ‘10 got an overwhelming response from the Pharma fraternity from all over the country.  Some of the prominent sponsors for Avalanche ’10 were pharmaceutical MNCs like Zydus Cadila, Torrent Pharma, Troikaa, Dishman and Claris Lifesciences.  Mr. Arjun Handa, CEO, Claris Lifesciences served as the chief guest at an Inauguration function. It received participation from students of Gujarat, Andhra pradesh, Maharashtra, Madhya Pradesh, and other states across the country.


With various interesting events in line like Pharma Marketing, Pharma Modelling, pharma Recipe, case study, quiz, etc... Avalanche'12 is all set to create a fury of thoughts amongst the masses. 


Various Events include: 


Quiz
Debate 
Pharma Marketing
Pharma Modelling 
Poster Presentation
Pharma Recipe
Case Study
Scitoons
Network Gaming
Youth Asssembly


For more information on the events, Click here

The Pharmablockbusters Team recommends this event strongly, as it has been scrunitizing the event since its inception, and all the Pharmacy students will definitely gain a lot from this  experience.

Registration Details:


Last Date for registration – 25th January 2012
Registration fees – Rs. 250/- per student
Mode of Payment: By Cash or At Par Cheque/DD in favour of “Ramanbhai Patel College of Pharmacy” payable at Anand.
For registration forms, Click here.

VENUE

Ramanbhai Patel College of Pharmacy, CHARUSAT Campus,Changa

Ta-Petlad,Dist-Anand 388421

Gujarat, India

CONTACT

Maharshi Raval- (+91) 9428805096

Sanket Shah- (+91) 9825313637

Email Address: avalanche12@charusat.ac.in

For More Information:

http://www.charusat.ac.in/avalanche12/index.html

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Bardoxolone: A potential Mega Blockbuster!!

Bardoxolone methyl (other names “RTA 402” and “CDDO-methyl ester”) is a synthetic oleananetriterpenoid that is an orally-available first-in-class antioxidant inflammation modulator (AIM). It is the most potent known inducer of the Keap1-Nrf2pathway to enter clinical development and works to suppress both oxidative stress and inflammation.

The drug: Bardoxolone

The Disease: Chronic Kidney Disease

The Develepors: Reata and Abott Pharma

Peak Projections: Several billion plus*

Bardoxolone methyl is currently being developed in late-stage clinical trials by Reata Pharmaceuticals, Inc. for the treatment of moderate to severe chronic kidney disease (CKD) in type 2 diabetes mellitus patients.

Pathogenesis:
Oxidative stress and inflammation are thought to be key drivers of the fibrotic process in CKD inducing structural changes within the glomerulus. 
Reactive Oxygen and Nitrogen species (ROS) activate NF-kB, which activates various pro-inflammatory mediators, resulting in oxidative stress.
This then results in chronic inflammation and fibrosis, thus causing chronic kidney diseases.

In vivo data indicates that the Keap-Nrf2 pathway is suppressed in models of kidney fibrosis whilst there is a simultaneous increase in oxidative stress and inflammation.Thus, activating this pathway, may lead to improved conditions in chronic kidney diseases.

Scientists at Reata Pharma, explored 
this pathway, and developed some compounds, which are potent inducers of the transcription factor Nrf2.

Nuclear factor-erythroid-related factor 2 (Nrf2) plays a critical  part in basal activity and coordinated induction of genes encoding numerous antioxidant and phase II detoxifying enzymes (including catalase, superoxide dismutase, glutathionse s-transferase etc.).






Mechanism of Action:
Bardoxolone, their most active compound, acts as an Anti-inflammation Mediators (AIMs) and activates Nrf2, causing causing increased production of over 250 antioxidant enzymes and resulting in the inhibition of pro-inflammatory transcription factors, such as NF-κB and STAT3.
Thus AIMS provide a vital mechanism based relief from oxidative stress and damage to the neprons, thus proving to be a key player in CKD clinical control.


Bardoxolone in Clinical Trials:
Clinical observations in Phase 2 studies with bardoxolone methyl have included the following:

• Significant and sustained improvements in eGFR.
• Increased creatinine clearance, with no decrease in 24-hour creatinine excretion.
• Parallel improvements in other measures of kidney function, including blood urea nitrogen and uric acid, which correlate with the improvement in eGFR.
• Persisting increase in eGFR from baseline following withdrawal of therapy (when the drug has largely been cleared out of the body).

Reata started enrolling patients for the Phase III on bardoxolone last summer. As per Reata CEO Warren Huff, the process is running ahead of schedule, leaving them on track to wrap in the summer of 2013 with a possible approval in 2014.

A Blockbuster deal: 

Recently,Reata Pharmaceuticals snagged a $450 million quick-cash deal with Abbott on the ex-U.S. rights to bardoxolone, which is the focus of a big pivotal study. Now Abbott, is committing itself to a long-term future with Reata in what amounts to an unusually large cash commitment to a preclinical venture.

In the deal, Abbott and Reata have agreed to share the costs and profits on the biotech's antioxidant inflammation modulators(AIM). The two companies also agreed to collaborate on discovery work related to other drugs that can be derived from the AIM program. The first human study of a preclinical drug covered by the partnership is slated to begin in 2012.

This treatment has the potential to dramatically change the treatment landscape,  Current therapies only modestly slow the progression of the disease, while bardoxolone has the potential to markedly improve patient outcomes. It has been proposed to lengthen the lives of patients without the need of undergoing the ardent task of constant dialysis.


With more varied implications of AIMs in many diseases like Parkinson's,alzheimers, Cancer, etc. due to its anti-oxidant and anti-inflammatory action, Bardoxolone sets the right parameters to be a potential Mega Blockbuster in the near future!!

*as per Fierce Pharma report.
Know more about clinical trials of Bardoxolone from: http://www.nejm.org/doi/pdf/10.1056/NEJMc1110239
To know more about Chronic kidney Disease, Click here

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