Thursday, January 31, 2013

Exjade Approved for Inherited Blood Disorder - Drugs.com MedNews

We know that, Deferasirox (marketed as Exjade) is a rationally-designed oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the USA for this purpose.
It was approved by the United States Food and Drug Administration (FDA) in November 2005. According to FDA (May 2007), renal failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. It is approved in the European Union by the European Medicines Agency (EMA) for children 6 years and older for chronic iron overload from repeated blood transfusions.
Now  Exjade (deferasirox) has been approved by the U.S. Food and Drug Administration to remove excess iron in the blood among people with a genetic blood disorder called non-transfusion-dependent thalassemia (NTDT). Too much iron in the blood can damage vital organs, the agency said Wednesday in a news release. 

Thalassemia typically leads to the production of fewer red blood cells and less hemoglobin, a protein that carries oxygen throughout the body. NTDT is a milder form of thalassemia that unlike other forms, does not require frequent blood transfusions. Thalassemia affects about 1,000 people in the United States, the FDA said............

Wednesday, January 30, 2013

NIH clinical trial begins for treatment of rare, fatal neurological disorder, January 23, 2013 News Release - National Institutes of Health (NIH)

 We know that, Cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). Cyclodextrins are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical,drug delivery, and chemical industries, as well as agriculture and environmental engineering. Hydroxypropyl Beta Cyclodextrin (HPβCD) is the chief active compound found in Procter and Gamble's deodorizing product "Febreze" under the brand name "Clenzaire".Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape.



A clinical trial to evaluate a drug candidate called cyclodextrin as a possible treatment for Niemann-Pick disease type C1 (NPC), a rare and fatal genetic disease has already started on 23rd Jan, 2012. Scientists from the NIH’s National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) will conduct the clinical trial at the NIH Clinical Center. Reaching this trial stage required collaboration among government, industry, patient advocacy groups and academic researchers.



Tuesday, January 29, 2013

New drug protects against side effects of chemotherapy

 A drug developed at Linköping University in Sweden protects against the side effects of cancer treatments while strengthening the effects on the tumour. An international drug evaluation is now starting up on a larger group of patients. 

The results of the studies with the compound, known as calmangafodipir  [Ca4Mn(DPDP)5], were published in the latest issue of the cancer journal Translational Oncology with Professor Rolf G. G. Andersson as the main author.


The research was initiated on a substance called mangafodipir MnDPDP (see structure below), which was used as a contrast media in magnetic resonance scans. But pharmacologists at LiU discovered that it also protected healthy cells in connection with cancer treatments.



"We found that the substance could affect the formation of oxygen radicals, which are a cause of side effects in chemotherapy," says Professor Andersson.


For example, the number of white blood cells decreases drastically in almost all the patients, which opens the door to infections that could even be fatal.


The researchers began with cell tests, and then went on to mice infected with cancer cells. The mice were treated with chemotherapy and were administered mangafodipir at the same time. Tumour formation decreased while white blood cells were protected.


One problem was that a large portion of the manganese in the substance was released; as a consequence, the positive effect subsided. The free manganese can also be poisonous and cause brain damage. More at the ffollowing link...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542842/

Monday, January 28, 2013

Beta carotene may protect people with common genetic risk factor for type-2 diabetes

Stanford University School of Medicine investigators have found that for people harboring a genetic predisposition that is prevalent among Americans, beta carotene, which the body converts to a close cousin of vitamin A, may lower the risk for the most common form of diabetes, while gamma tocopherol, the major form of vitamin E in the American diet, may increase risk for the disease. 


Sunday, January 27, 2013

Drug combination extends pancreatic cancer patient survival, study suggests

A multi-center Phase III clinical trial demonstrates that Abraxane (below left structure) (nab-paclitaxel) plus gemcitabine is the first combination of cancer drugs to extend survival of late-stage pancreatic cancer patients compared to standard treatment. Their findings show that Abraxane plus gemcitabine (below right structure) was well tolerated and resulted in clinically meaningful outcomes compared to gemcitabine alone, the current standard of care. 


MPACT is the largest phase III clinical trial completed in advanced pancreatic cancer with more than 800 patients. Findings from the study showed a 59 percent increase in one-year median survival rates from less than a quarter of the patients (22 percent) to more than a third (35 percent). The two-year survival rate for this cancer is negligible, less than 4 percent, but that more than doubles (9 percent) with the nab-paclitaxel/gemcitabine combination.

The study showed significant improvement among some of the sickest patients including those with increased metastases. Significantly there was no increase in life-threatening toxicity. Other drug combinations that have demonstrated benefit have been limited by increased toxicities.

"This is a major improvement in a cancer with the lowest survival rates among all cancer types," said Dr. Ramesh Ramanathan, medical director of Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare and principal investigator for the clinical trial in the United States. "Advanced pancreatic cancer is fourth most common cause of cancer death in the United States and throughout the world. It is difficult to diagnose with a majority of the cases diagnosed at a late stage after the disease has already advanced."

Saturday, January 26, 2013

Novel technique reveals dynamics of telomere DNA structure: Chromosome-capping telomeres are a potential target for anti-cancer drugs

In continuation of my update on telomerase
"Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure."


Researchers used  "magnetic tweezers" system to stretch the DNA molecule, while a fluorescence microscopy technique was used to monitor small-scale structural changes in the DNA. 
"Unlike other DNA structures, the G-quadruplex structure is fairly brittle. It takes very little perturbation to make the whole thing fall apart," Stone said. "We also found that the unfolded state has a highly compacted conformation, which tells us that it still has interactions that favor the folding reaction."
These findings have implications for understanding the molecular mechanisms of telomere-associated proteins and enzymes involved in the unfolding reaction, as well as for rational design of anti-cancer drugs, Stone said. Small molecules that bind to and stabilize telomere DNA G-quadruplexes have shown promise as anti-cancer drugs.

The integration of fluorescence measurements and magnetic tweezers is a powerful method for monitoring DNA structural dynamics, and as biophysical techniques go, it is not hard to implement, Stone said. His lab worked with DNA molecules containing the G-quadruplex sequence from human telomere DNA, attaching one end of the DNA to a glass slide and the other end to a tiny magnetic bead. A magnet held above the sample pulled on the bead, exerting a stretching force on the DNA molecule that varied according to how close the magnet was to the sample.

Ref : http://nar.oxfordjournals.org/content/early/2013/01/08/nar.gks1341


Takeda Receives FDA Approval for Oseni (alogliptin and pioglitazone) for Type 2 Diabetes

In continuation of y update on pioglitazone

Takeda Pharmaceutical Company Limited (Takeda) and its wholly-owned subsidiary, Takeda Pharmaceuticals U.S.A., Inc. today announced that the United States (U.S.) Food and Drug Administration (FDA) has approved Oseni (alogliptin and pioglitazone) for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise.

Thursday, January 24, 2013

NuPathe's Zecuity Approved by the FDA for the Acute Treatment of Migraine

We know that, Sumatriptan (see structure) is a synthetic drug belonging to the triptan class, used for the treatment of migraine headaches. Structurally, it is an analog of the naturally occurring neuro-active alkaloids dimethyltryptamine (DMT), bufotenine, and 5-methoxy-dimethyltryptamine, with an N-methyl sulfonamidomethyl- group at position C-5 on the indole ring. On an 17, 2013, FDA has approved, Zecuity (sumatriptan iontophoretic transdermal system) for the acute treatment of migraine with or without aura in adults. Zecuity is a single-use, battery-powered patch that actively delivers sumatriptan, the most widely prescribed migraine medication, through the skin. Zecuity provides relief of both migraine headache pain and migraine-related nausea (MRN)....



Tuesday, January 22, 2013

Researchers identify potential sources of medicines derived from plants against diabetes

A group of researchers from the university's School of Science, led by Dr Solomon Habtemariam, believe they have identified potential sources of medicines derived from plants which may have fewer adverse side-effects for diabetes sufferers.

The scientists are investigating the properties of two plants found in south-east Asia which they think could have properties that are not only anti-diabetic, but also lipid- or fat-lowering, and so can help tackle obesity. The researchers at Greenwich aim to isolate and identify certain extracts from the plants Cassia auriculata and Cassia alata, which could have 'active ingredients' for treating diabetes. They discovered that one of the compounds isolated from the plant, kaempferol 3-O-rutinoside, (structure below)  has proved to be more than eight times more potent than the standard anti-diabetic drug, acarbose.  



The team also found the plants have anti-oxidant properties, which is beneficial when treating diabetes.


"Our other most interesting finding is that many of the active ingredients from the Cassia auriculata plant work through a process called 'synergism' - in other words, they work together to produce an effect greater than the sum of their individual effects," Dr Habtemariam says. "Overall, this suggests that the crude plant extract has lots of potential to be used clinically for treating diabetes and associated diseases."

The researchers adds that the research  is ongoing and requires further study and validation, in my opinion it is interesting...

Ref : http://www2.gre.ac.uk/about/news/articles/2012/a2410-drugs-for-diabetes-scientists-test-the-power-of-plants

Sunday, January 20, 2013

Universität Bern - Abteilung Kommunikation - Gute Bakterien im Darm beugen Diabetes vor

Universität Bern - Abteilung Kommunikation - Gute Bakterien im Darm beugen Diabetes vor

Tamoxifen can counteract some pathologic features in mouse model of DMD

 In continuation of my update on Tamoxifen

Using the mdx5Cv mouse model of DMD, investigators found that tamoxifen, given orally for more than a year, "caused remarkable improvements of muscle force and of diaphragm and cardiac structure," according to lead author Olivier M. Dorchies, PhD, of the Department of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences of the University of Geneva and University of Lausanne. For instance, in the heart, fibrosis was diminished by approximately 50%. In the diaphragm, the muscle of the dystrophic mouse thought to be most like that of human DMD, tamoxifen reduced fibrosis while increasing thickness as well as the number and average diameter of muscle fibers. The net effect was that tamoxifen raised the amount of contractile tissue available for respiration by 72%.


Patients with DMD show muscle degeneration, and their muscle fibers become abnormally susceptible to stress. In this animal study, tamoxifen improved the structure of leg muscles, slowed muscle contraction, increased overall muscle function, and made leg muscles more resistant to repetitive stimulation and fatigue. In fact, tamoxifen rendered dystrophic muscles even stronger than those of non-dystrophic control mice. "Our findings of a slower rate of contraction and an enhanced resistance to fatigue in muscles from tamoxifen-treated dystrophic mice are of significance for the pathophysiology of muscular dystrophy," say the authors.


More : http://www.journals.elsevierhealth.com/periodicals/ajpa/article/S0002-9440%2811%2901061-3/abstract
 

p53 activation suppresses malic enzyme expression and leads to senescence in pre-cancerous cells

A team of researchers from the Perelman School of Medicine, University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates. Researchers describes that, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism.(The Yang lab identified p53's role in glucose metabolism in the past.)


The new findings, Yang  (lead researcher) says, suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells.


"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang says.


Significantly, the findings also identify malic enzymes as novel and potentially useful pharmaceutical targets for anticancer therapy, as well as possible mediators of the normal aging process   though neither possibility was actually addressed in the current study.


As cells become damaged and precancerous, the p53 protein prevents those cells from continuing towards becoming tumors by causing the cells to senesce. Metabolic cues also regulate senescence, but the molecular relays coupling those two processes,  senescence and metabolism  remained unknown................

Saturday, January 19, 2013

Diospyrin inactivates a drug target for tuberculosis in new way

A compound from the South African toothbrush tree inactivates a drug target for tuberculosis in a previously unseen way. 


The compound under research, diospyrin (see below structure), binds to a novel site on a well-known enzyme, called DNA gyrase, and inactivates the enzyme. DNA gyrase is essential for bacteria and plants but is not present in animals or humans. It is established as an effective and safe drug target for antibiotics.


"The way that diospyrin works helps to explain why it is effective against drug-sensitive and drug-resistant strains of tuberculosis," said Professor Tony Maxwell from the John Innes Centre.

In traditional medicine the antibacterial properties of the tree are used for oral health and to treat medical complaints such bronchitis, pleurisy and venereal disease. Twigs from the tree are traditionally used as toothbrushes.



Most antibiotics originate from naturals sources, such as the soil bacteria Streptomyces. Antibiotics derived from plants are less common, but they are potentially rich sources of new medicines.

"Extracts from plants used in traditional medicine provide a source for novel compounds that may have antibacterial properties, which may then be developed as antibiotics," said Professor Maxwell.


Friday, January 18, 2013

Beta blocker use linked to NSCLC patient survival

Analysis shows that the 155 NSCLC patients given incidental beta blockers had significant better distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival than the 567 patients who were not given the agents.

However, beta blocker use had no impact on locoregional progression-free survival (LRPFS), leading the researchers to suggest that "the drugs may be affecting the tumor metastatic cascade rather than affecting the primary tumor."

The team investigated the impact of beta blockers on newly diagnosed NSCLC patients at the MD Anderson Cancer Center between 1998 and 2010 following reports that norepinephrine may stimulate tumor cell migration - a process could be targeted via the beta-adrenergic receptor.

Beta blocker use significantly predicted longer DMFS (hazard ratio [HR]=0.67), DFS (HR=0.74), and OS (HR=0.78), after adjusting for confounders including age, cancer stage, histology, tumor volume, Karnofsky performance score, use of concurrent chemotherapy, and radiation dose. Other factors including presence of hypertension or chronic obstructive pulmonary disease, and use of aspirin were also considered in the multivariate analysis.
The researchers note that 68% of patients were given beta blockers for hypertension. The remaining patients were given beta blockers for nonhypertensive disorders such as coronary heart disease.



Most patients were given selective (β1) beta blockers such as metoprolol (n=89)(left structure) and atenolol (above right structure)(n=43). Just 21 of the patients were given nonselective agents, such as carvedilol.

Thursday, January 17, 2013

Biguanide mechanism discovered

For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs....

Wednesday, January 16, 2013

Melanomas that develop resistance to vemurafenib also become addicted to the drug

In continuation of my update on vemurafenib

Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease. 

The team, based at the University of California, San Francisco (UCSF), the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, Calif., and University Hospital Zurich, found that one mechanism by which melanoma cells become resistant to vemurafenib also renders them "addicted" to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.


Ref : http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11814.html


Tuesday, January 15, 2013

Results from Morphotek’s farletuzumab Phase III combination study on ovarian cancer

In continuation of my update on carboplatin and a taxane


Morphotek® Inc., a wholly-owned subsidiary of Eisai Inc., announced top-line results from a Phase III study of its investigational agent farletuzumab (MORAb-003) in combination with carboplatin and a taxane in patients with platinum-sensitive epithelial ovarian cancer in first relapse. 

The study found that farletuzumab in combination with carboplatin and a taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing.

The preliminary safety analysis indicated that the most commonly reported adverse events were those known to be associated with the study chemotherapy agents. Additionally, some immune-mediated events were observed with farletuzumab.

After further analysis of these clinical results, the company will determine a new development strategy based on discussion with external experts and relevant health authorities. In the double-blind, placebo-controlled study, 1,100 patients were enrolled to receive standard-of-care (carboplatin and a taxane [paclitaxel or docetaxel]) chemotherapy and were randomized to three parallel groups to receive one of two different dose levels of farletuzumab or placebo.

"While we are disappointed with these results, we know that ovarian cancer is a difficult disease to treat successfully," says Dr. Nicholas Nicolaides , President and CEO of Morphotek. "Morphotek remains committed to research to understand the potential role of farletuzumab in ovarian and other types of cancer."......


Monday, January 14, 2013

Melanomas that develop resistance to vemurafenib also become addicted to the drug

Vemurafenib (marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. The name "vemurafenib" comes from V600E mutated BRAF inhibition.
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,  Health Canada approval on February 15, 2012 and on February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer....

Mechanism : Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. 

Saturday, January 12, 2013

FDA approves Kineret for the treatment of NOMID


Anakinra is an interleukin-1 (IL-1) receptor antagonist. Anakinra blocks the biologic activity of naturally occurring IL-1, includinginflammation and cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in many tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunologic reactions. IL-1 additionally stimulates bone resorptionand induces tissue damage like cartilage degradation as a result of loss of proteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist is not found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients.
Anakinra is not considered a 'Disease-modifying antirheumatic drug' (DMARD) but rather a 'Biological Response Modifier' (BRM) because its able to selectively target the pathologic element of the disease.

FDA approves Kineret for the treatment of NOMID

Wednesday, January 9, 2013

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

In continuation of my update on Sirturo

On Dec. 28, the U.S. Food and Drug Administration approved Sirturo (bedaquiline) as part of combination therapy to treat adults with multi-drug resistant pulmonary tuberculosis (TB) when other alternatives are not available.


Bedaquiline (also known as SirturoTMC207 or R207910 see structure) is an diarylquinoline anti-tuberculosis drug, which was discovered by Koen Andries and his team at Janssen Pharmaceutica. It was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting Late-Breaker Session, after the drug had been in development for over 7 years, and a trial of 47 patients showed that it is effective in the treatment of M. tuberculosis.

Multi-drug resistant TB occurs when M. tuberculosis becomes resistant to isonazid and rifampin, two powerful drugs most commonly used to treat TB. Sirturo is the first drug approved to treat multi-drug resistant TB and should be used in combination with other drugs used to treat TB. Sirturo works by inhibiting an enzyme needed by M. tuberculosis to replicate and spread throughout the body.
“Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who have don’t have other therapeutic options available,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options.”
Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.
The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.
Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.



Tuesday, January 8, 2013

FDA Approves Fulyzaq - First Anti-Diarrheal Drug for HIV/AIDS Patients

We know that, Crofelemer (USAN, trade name Fulyzaq) is a drug under development for the treatment of diarrhoea associated with anti-HIV drugs such as nucleoside analog reverse transcriptase inhibitors and protease inhibitors. Other possible uses include diarrhoea in children, acute infectious diarrhoea, and diarrhoea in patients with irritable bowel syndrome. It was initially developed by Napo Pharmaceuticals, which licensed it to Glenmark Pharmaceuticals in 140 emerging markets and to Salix Pharmaceuticals in the US, EU and some other markets.

On 31st Dec, 2012, U.S. Food and Drug Administration today approved Fulyzaq (crofelemer) to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy, a combination of medicines used to treat HIV infection....

Monday, January 7, 2013

New class of malaria drugs using essential calcium enzyme developed


Greenbaum and his collaborators examined the crystal structure of calpastatin, a natural calpain inhibitor, for clues. They decided to take a different tack on inhibitor development, which has traditionally been designing small peptide-like inhibitors that fit across an enzyme's active site. Studying the configuration of how calpastatin bound to the active site of the calpain complex, researchers found that there was a small alpha-helix that fit into the active site of the calpain enzyme.


Researchers have never before used an alpha-helix structure to inhibit a protease. "Traditionally people thought that alpha helices normally make horrible inhibitors because it was thought that proteases don't like to bind to them preferring to bind motifs called a beta-sheet," Greenbaum notes. The research team created a peptide with an alpha-helical shape that would fit into the active site of the calpain protease.

The team set out to find a way to stabilize the helix by modifying it with a cross-linking peptide. They screened twenty-four commercially available crosslinkers, identifying five that succeeded in stabilizing the helix. They selected one in particular  dibromo-m-xylene c15 and used it to mimic a protein-protein interaction between calpain and calpastatin. By binding to the active site and thus blocking it, the synthesized molecule inhibits the calpain enzyme from binding with other molecules that permit it to wreak its damaging effects.
"It's the first example of an alpha-helical inhibitor of any protease," Greenbaum says. "Previously no one's ever tried using an alpha-helical motif. It opens up a new way of inhibiting proteases." Aside from being a good inhibitor, the stabilized alpha-helical molecule is also highly specific for calpains, while ignoring other, similar-shaped proteases, thus hopefully downplaying potential side effects if used in humans.
Greenbaum and his collaborators are building upon this initial success to expand the basic concept to a wide range of protease molecules. "The next step is to show how this concept can be generalized to multiple classes of proteases, many of which are pharmaceutically of great interest," he explains. "It's not a single-hit wonder."
The extension of the technique to stabilize the alpha-helix shape in enzymes to other proteins could eventually lead to practical drug therapies for a wide range of diseases, predict the researchers.

Ref : http://pubs.acs.org/doi/abs/10.1021/ja307599z


Sunday, January 6, 2013

Common cholesterol-lowering drug may help protect against cerebral malaria

In continuation of my update lovastatin

Researchers have discovered that adding lovastatin, a widely used cholesterol-lowering drug, to traditional antimalarial treatment decreases neuroinflammation and protects against cognitive impairment in a mouse model of cerebral malaria. Although there are differences between mouse models of cerebral malaria and human disease, these new findings indicate that statins are worthy of consideration in clinical trials of cerebral malaria. 


Statins, a class of drugs best known for their ability to lower cholesterol, have also been shown to be active in modulating a variety of immune system responses. In their research, Zimmerman and his Brazilian colleagues evaluated the effect of statins in a mouse model of cerebral malaria. The researchers found that adding a drug called lovastatin to traditional antimalarial therapy prevented cognitive dysfunction in mice infected with cerebral malaria. They discovered that addition of lovastatin decreased white blood cell accumulation and leakiness in blood vessels in the brain. Lovastatin also reduced production of damaging oxygen-containing molecules and other factors that promote inflammation.


"The molecular mechanisms that give rise to cerebral malaria and subsequent cognitive dysfunction are not yet known," says Zimmerman. "However, the fact that statin treatment decreases both injurious blood vessel inflammation and cognitive dysfunction suggests that a combination of vascular and inflammatory triggers leads to cerebral pathology and intellectual deficits."
Ref : http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003099

Common cholesterol-lowering drug may help protect against cerebral malaria

Saturday, January 5, 2013

Aeterna Zentaris reaches SPA agreement with FDA for AEZS-108 Phase 3 trial in endometrial cancer


Aeterna Zentaris Inc. announced that it has reached an agreement with FDA  on a Special Protocol Assessment ("SPA") for an upcoming Phase 3 registration trial in endometrial cancer with its doxorubicin peptide conjugate, AEZS-108. The SPA agreement states that the proposed trial protocol design, clinical endpoints and planned analyses are acceptable to the FDA to support a regulatory submission. 

About AEZA-108 : AEZS-108: AEZS-108 (AN-152, or zoptarelin doxorubicin) is a targeted cytotoxic peptide conjugate which is a hybrid molecule composed of a synthetic peptide carrier and a well-known cytotoxic agent, doxorubicin. The design of this product allows for the specific binding and selective uptake of the cytotoxic conjugate by the LHRH receptor-positive tumors. The binding of conjugate molecule AEZS-108 to cancerous cells that express these receptors results in its accumulation in the malignant tissue. This binding is followed by internalization and retention of the cytotoxic drug, doxorubicin, in the cells. Therefore, since they target specific cells, cytotoxic conjugates are postulated to be more effective and have less side-effects than the respective non-conjugated/non-linked cytotoxic agents in inhibiting tumor growth. AEZS-108 is the first drug in a clinical study that targets the cytotoxic activity of doxorubicin specifically to LHRH-receptor expressing tumors. 


"We are pleased with the agreement with the FDA which provides us with a clearly defined development and regulatory pathway for AEZS-108 in endometrial cancer", stated Juergen Engel , PhD, President and CEO at Aeterna Zentaris. "AEZS-108's innovative targeted approach could offer a new treatment option for women with endometrial cancer and provide the Company with a significant market opportunity."

Friday, January 4, 2013

Drug May Help Women Who Quit Smoking Avoid Weight Gain - Drugs.com MedNews

In continuation of my update on Naltrexone

We know that, Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloridesalt, naltrexone hydrochloride, and marketed under the trade names Revia andDepade. In some countries including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol. Also in the US, Methylnaltrexone Bromide, a closely related drug, is marketed as Relistor, for the treatment of opioid induced constipation.

Naltrexone should not be confused with naloxone (which is used in emergency cases of overdose rather than for longer-term dependence control) nor nalorphine. Using naloxone in place of naltrexone can cause far worse withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead to insufficient opiate antagonism and fail to reverse the overdose.



Thursday, January 3, 2013

FDA Approves Juxtapid - New Orphan Drug for Rare Cholesterol Disorder

In continuation of my update on Juxtapid (lomitapide) 

We know that, Lomitapide (INN) is an investigational drug for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals.  It has been tested in several Phase II clinical trials as single treatment and in combinations with atorvastatinezetimibe and fenofibrate. 

The US Food and Drug Administration approved lomitapide on December 21, 2012 as anorphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia (HoFH).



FDA Approves Juxtapid - New Orphan Drug for Rare Cholesterol Disorder