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

 

Tamoxifen can counteract some pathologic features in mouse model of DMD

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................

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

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.

Diospyrin inactivates a drug target for tuberculosis in new way

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.

Beta blocker use linked to NSCLC patient survival

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....

Biguanide mechanism discovered

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

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

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."......

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

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. 

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

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

Hydrogen peroxide vapor enhances hospital disinfection of superbugs

Hydrogen peroxide vapor enhances hospital disinfection of superbugs

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 Sirturo, TMC207 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.

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

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....

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

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

New class of malaria drugs using essential calcium enzyme developed

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