Study offers new hope for treatment of diffuse large B-cell lymphoma

Study offers new hope for treatment of diffuse large B-cell lymphoma

Compound Anthracimycin, discovered at sea shows potency against anthrax

Fenical's team in the Scripps Center for Marine Biotechnology and Biomedicine, working in conjunction with San Diego-based Trius Therapeutics, used an analytical technique known as spectroscopy to decipher the unusual structure of a molecule from a microscopic species known as Streptomyces. Initial testing of the compound, which they named anthracimycin, revealed its potency as a killer of anthrax, the infectious disease often feared as a biological weapon, as well as MRSA.

"The real importance of this work is the fact that anthracimycin has a new and unique chemical structure," said Fenical, who added that the finding is a basic research discovery, which could lead to testing and development, and eventually a drug. "The discovery of truly new antibiotic compounds is quite rare. This discovery adds to many previous discoveries that show that marine bacteria are genetically and chemically unique."

The discovery provides the latest evidence that the oceans, and many of its unexplored regions, represent a vast resource for new materials that could one day treat a variety of diseases and illnesses. Fenical, a distinguished professor of oceanography and pharmaceutical science, helped found the field of marine biomedicine as a researcher at Scripps. He is a pioneer in discovering and identifying these novel compounds. His research has helped bring attention to the need for continued exploration of the ocean for science and society....

More at  https://scripps.ucsd.edu/news/13060

Ref : http://onlinelibrary.wiley.com/doi/10.1002/anie.201302749/abstract

Compound discovered at sea shows potency against anthrax

Drug shows dramatic reduction in seizures in patients with tuberous sclerosis complex

In continuation of my update on Everolimus

Newest study, led by a physician-scientist at Cincinnati Children's in collaboration with a team at Texas Children's Hospital in Houston, has been accepted by the journal Annals of Neurology, and is available online.

"Everolimus treatment reduced seizure frequency and duration in the majority of TSC epilepsy patients whose seizures previously did not respond to treatment," says Darcy Krueger, MD, PhD, a pediatric neurologist at Cincinnati Children's and lead author of the study. "This improvement in seizure control was associated with a better quality of life, and side effects were limited. Work is already underway to confirm these results in a follow-up, phase III clinical study."

"This has been positively life-changing for the patients involved and is nothing short of transformative in the treatment of epilepsy associated with cellular growth disorders, such as TSC," says Angus Wilfong, MD, director of the comprehensive epilepsy program at Texas Children's Hospital and associate professor of pediatrics and neurology at Baylor College of Medicine.

The study included 20 patients who were treated with everolimus. Their median age was 8. Half of the patients were enrolled at Cincinnati Children's and half at Texas Children's Hospital in Houston.

The researchers found that everolimus reduced seizure frequency by at least 50 percent in 12 of the 20 participants. The drug also reduced seizures in 17 of the 20 TSC patients by a median rate of 73 percent. Four patients were free of seizures and seven had at least a 90 percent reduction in seizure frequency.

Overall quality of life, as reported by the participants' parents, also improved. Parents reported several positive changes, including attention, behavior, social interaction and physical restrictions.

Ref: http://onlinelibrary.wiley.com/doi/10.1002/ana.23960/abstract;jsessionid=5F1A5FDF269D16EDA880D9A0CE57B8CC.d03t03

Drug shows dramatic reduction in seizures in patients with tuberous sclerosis complex

How cranberries impact infection-causing bacteria

In continuation of my update on Cranberries

Researchers in McGill University's Department of Chemical Engineering are shedding light on the biological mechanisms by which cranberries may impart protective properties against urinary tract and other infections. Two new studies, spearheaded by Prof. Nathalie Tufenkji, add to evidence of cranberries' effects on UTI-causing bacteria. The findings also point to the potential for cranberry derivatives to be used to prevent bacterial colonization in medical devices such as catheters.

In research results published online last month in the Canadian Journal of Microbiology, Prof. Tufenkji and members of her laboratory report that cranberry powder can inhibit the ability of Proteus mirabilis, a bacterium frequently implicated in complicated UTIs, to swarm on agar plates and swim within the agar. The experiments also show that increasing concentrations of cranberry powder reduce the bacteria's production of urease, an enzyme that contributes to the virulence of infections.

These results build on previous work by the McGill lab, showing that cranberry materials hinder movement of other bacteria involved in UTIs. A genome-wide analysis of an uropathogenic E. coli revealed that expression of the gene that encodes for the bacteria's flagellar filament was decreased in the presence of cranberry PACs.

The team's findings are significant because bacterial movement is a key mechanism for the spread of infection, as infectious bacteria literally swim to disseminate in the urinary tract and to escape the host immune response.

"While the effects of cranberry in living organisms remain subject to further study, our findings highlight the role that cranberry consumption might play in the prevention of chronic infections," Tufenkji says. "More than 150 million cases of UTI are reported globally each year, and antibiotic treatment remains the standard approach for managing these infections. The current rise of bacterial resistance to antibiotics underscores the importance of developing another approach."

Ref : http://www.nrcresearchpress.com/doi/abs/10.1139/cjm-2012-0744#.UeTskY03C3E

How cranberries impact infection-causing bacteria

Phase III study: REVLIMID meets primary endpoint in patients newly diagnosed with multiple myeloma

In continuation of my update on lenalidomide

Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG), recently announced that its phase III study (MM-020/IFM 07-01) of REVLIMID®(lenalidomide) in combination with dexamethasone in patients newly diagnosed withmultiple myeloma met its primary endpoint of progression-free survival (PFS). In the study, a doublet regimen of continuous oral lenalidomide in combination with low-dose dexamethasone (Rd) demonstrated a statistically significant improvement in PFS compared to patients receiving a comparator arm with a triplet regimen consisting of melphalan, prednisone and thalidomide (MPT).

Phase III study: REVLIMID meets primary endpoint in patients newly diagnosed with multiple myeloma

Scientists set out to develop safer versions of acetaminophen

Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intramolecular electron transfer that generates the Tyr385 radical required for abstraction of a hydrogen from arachidonic acid to initiate prostaglandin synthesis. Unrelated to this pharmacological action, metabolism of ApAP by CYPs yields an iminoquinone electrophile that is responsible for the hepatotoxicity, which results from high doses of the drug. Researchers synthesized novel heterocyclic phenols predicted to be electron donors. Two of these inhibited the oxygenation of arachidonic acid by PGHS-1 and myoglobin and also were shown to be more metabolically stable and exhibited less direct cytotoxicity than acetaminophen. They are leading candidates for studies to determine whether they are free of the metabolism-based hepatotoxicity produced by acetaminophen.....

Ref : http://pubs.acs.org/doi/pdf/10.1021/ml4000904

Scientists set out to develop safer versions of acetaminophen

Urocortin molecule protects cells from osteoarthritis, say researchers

We know that, Urocortin is a protein that in humans is encoded by the UCN gene. This gene is a member of the sauvagine/corticotropin-releasing factor/urotensin I family. It is structurally related to the corticotropin-releasing factor (CRF) gene and the encoded product is an endogenous ligand for CRF type 2 receptors. In the brain, it may be responsible for the effects of stress on appetite. In spite of the gene family name similarity, the product of this gene has no sequence similarity to urotensin II. Urocortin is a potent anorexigenic peptide of 40 amino acids that induces fed-like motor activity when administered centrally or peripherally in fasted animals. Urocortin belongs to the corticotropin-releasing factor (CRF) family that includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is also a potent and long-lasting hypotensive agent and increases coronary blood flow.

Now researchers from The University of Manchester and the University of Westminster have found that the molecule, known as Urocortin, protects cells in the joints from being destroyed.

The discovery could help lead to the development of new medicines to prevent joint degradation  a condition which affects millions of people in the UK each year.

Merck Receives Complete Response Letter for Suvorexant, Merck’s Investigational Medicine for Insomnia

In continuation of my update on Suvorexant

New Drug Application Submitted to U.S. FDA for Ibrutinib in the Treatment of Two B-Cell Malignancies

We know that, Ibrutinib, also known as PCI-32765, is an experimental drug candidate for the treatment of various types of cancer. It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton tyrosine kinase (Btk). Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson's Janssen.

Now Janssen Research & Development, LLC announced the submission of a New Drug Application for ibrutinib to the U.S. Food and Drug Administration (FDA) for its use in the treatment of previously treated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and for its use in the treatment of previously treated patients with mantle cell lymphoma (MCL). The regulatory submission for ibrutinib is supported by data from two pivotal Phase 2 studies, one in relapsed/refractory CLL/SLL (PCYC-1102) and one in relapsed/refractory MCL (PCYC-1104), both of which were published in The New England Journal of Medicine online on June 19, 2013. Ibrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor being jointly developed by Janssen and Pharmacyclics, Inc. for the treatment of B-cell malignancies.

New class of highly potent antimalarial compounds discovered

In a recent work published online today in the journal PNAS, researchers at the Instituto de Medicina Molecular (IMM), in Lisbon, Portugal, have discovered a new class of highly potent antimalarial compounds. These compounds, referred to as Torins, were originally developed by researchers in the Boston, MA to inhibit a key human protein involved in cell growth, mTOR, and have been shown to be effective anticancer agents in rodent models. In research perdormed by Dr. Kirsten Hanson in the laboratory of Dr. Maria Mota, the IMM team and their collaborators have discovered that Torins are extremely effective multistage antimalarials; Torins appear to have a novel activity against the Plasmodium parasites themselves, distinct from both currently used malaria therapeutics and from their ability to target human mTOR.

Torins are capable of killing the cultured blood stages of the human parasite, Plasmodium falciparum, the species which causes most malaria deaths and severe disease, and are equally potent against the liver stages of a model rodent parasite. A single dose of the compound Torin2 delivered at the beginning of the P. berghei liver stage is sufficient to eliminate infection in mice before any Plasmodium parasites reach the blood. "Given the alarming trend of resistance to our current antimalarial therapies, this is really an exciting finding," says Dr. Mota, the senior author of the study, "and we are already working to develop Torin molecules suitable for clinical trials of antimalarial activity in humans."

 Ref : http://www.pnas.org/content/early/2013/07/03/1306097110.full.pdf+html

New class of highly potent antimalarial compounds discovered

Scientists show how DHA resolves inflammation

In continuation of my update on DHA.

Chronic inflammation is a major factor in a wide range of problems from arthritis to cardiovascular disease, and DHA (struct above, found in fish oil) is known to temper this problem. A new research report appearing in the July 2013 issue of The FASEB Journal, helps explain why DHA is important in reducing inflammation, and provides an important lead to finding new drugs that will help bring people back to optimal health. Specifically, researchers found that macrophages (a type of white blood cell) use DHA to produce "maresins," (struct below) which serve as the "switch" that turns inflammation off and switches on resolution...

Scientists show how DHA resolves inflammation

The ribosome: New target for antiprion medicines

New research results from Uppsala University, Sweden, show that the key to treating neurodegenerative prion diseases such as mad cow disease and Creutzfeldt-Jakob disease may lie in the ribosome, the protein synthesis machinery of the cell. The results were recently published in the Journal of Biological Chemistry.

"We have now shown that the protein folding activity of the ribosome (PFAR) is most likely involved in prion propagation and thus, can be a specific target for antiprion medicines. If we understand the mechanism fully, we will be able to find ways to stop that too.," says Suparna Sanyal, senior lecturer at the Department of Cell and Molecular Biology, Uppsala University .

The ribosome is the protein synthesis machinery of the cell. The mechanism of protein synthesis by the ribosome is well characterized, while PFAR is a rather recent discovery. PFAR is a ribosomal RNA dependent function of the large subunit of the ribosome irrespective of its source. The PFAR center closely overlaps the peptidyl transferase center although the nucleobases responsible for these two functions are not all common.

"Our results show that two prion inhibitors 6-aminophenanthridine (left struct) and guanabenz acetate (right struct) implement antiprion activity by binding to ribosomal RNA and inhibiting PFAR. Thus, the ribosome and more specifically PFAR is the new target for antiprion medicines. Furthermore, we have developed an in vitro PFAR assay, which can be used as a platform for screening prion inhibitors in a high-throughput fashion. This assay is much more time and cost-effective than standard prion assays," says Suparna Sanyal....

 The ribosome: New target for antiprion medicines

 

Salsalate lowers blood glucose in type 2 diabetes, study suggests

In continuation of my update on Salsate

Joslin scientists report that salsalate, a drug used to treat arthritis, lowers blood glucose and improves glycemic control in type 2 diabetes. These findings, which were published today by the Annals of Internal Medicine, provide additional evidence that salsalate may be an effective drug to treat type 2 diabetes.

Ref : http://annals.org/article.aspx?articleid=1700640

Salsalate lowers blood glucose in type 2 diabetes, study suggests

Scientists identify promising antiviral compounds

Based on studies of the atomic-level structure of an enzyme that's essential for the maturation of adenovirus and how that enzyme becomes active  conducted at Brookhaven's National Synchrotron Light Source (NSLS) -- we used computational modeling to search for compounds that might interfere with this enzyme and tested the best candidates in the lab."

Out of 140,000 compounds in a national database, the scientists identified two they expect to be able to turn into antiviral agents to combat adenovirus.

This research is a great example of the potential for rational drug design…based on studies of the atomic-level structure of an enzyme…conducted at Brookhaven's National Synchrotron Light Source.

The need for such antiviral compounds stems from the diversity of human adenoviruses and their ubiquitous effects, Mangel said. Adenoviruses cause many types of respiratory diseases (including outbreaks among military recruits), childhood pneumonias, and eye infections -- and may even play a role in obesity. They are particularly dangerous for individuals with impaired immunity, such as transplant recipients and patients with AIDS.

With more than 50 varieties causing this range of diseases, it's unlikely scientists will develop a universally effective vaccine to prevent all strains of adenovirus before infection, Mangel said. But one thing all adenovirus strains share is a common mechanism of making new virus particles once an infection takes root. Targeting that mechanism with antiviral drugs -- the approach taken by the Brookhaven team -- may be a viable way to battle all adenovirus strains.

Mangel worked with fellow Brookhaven scientists William McGrath and Vito Graziano, along with Kathy Zabrocka, a student from Stanford University who was conducting an undergraduate internship in his lab. The research built on work Mangel's lab initiated years earlier to decipher the atomic-level structure of the adenovirus proteinase, an enzyme conserved throughout all strains of the virus that cleaves proteins during the assembly of new virus particles.

"Once those proteins are cleaved, the newly synthesized virus particle is infectious," Mangel explained. "If those proteins are not cleaved, then the infection is aborted. Thus, inhibitors of the adenovirus proteinase should be effective antiviral agents against all strains of adenovirus," he said.

Over several years, Mangel's group found that the activity of the enzyme was highly regulated by two cofactors, a small piece of another adenovirus protein and the viral DNA. Structures of the enzyme alone and in the presence of its cofactors, determined by x-ray crystallography at the NSLS, revealed key regions that could serve as potential targets for blocking the enzyme's activation or protein-cleaving ability.

"All that remained was to find compounds that bind to these targets to prevent the enzyme from functioning," Mangel said.

To find these compounds, the scientists used a technique called DOCKing, which entails computationally probing a region of the protein structure against databases of small molecules to determine which might bind most strongly. Out of a database of 140,000 potential compounds, the scientists identified 30 molecules predicted to fit best and ordered samples to test for inhibitor activity.

Two of the molecules (NSC-36806-left struct;  and NSC37249 right struct) that DOCKing identified turned out to be excellent inhibitors of the adenovirus proteinase. At the concentrations that inhibited the adenovirus proteinase, these same compounds did not inhibit other, similar enzymes. Thus, the compounds appear to be specific inhibitors of the adenovirus enzyme.

Ref : http://www.sciencedirect.com/science/article/pii/S0014579313003876  

The molecules identified are still too large to be delivered as drugs. So the scientists are working to pare down the size in the design of a second-generation compound based upon the binding portions of the two inhibitors. This new molecule is expected to readily enter adenovirus-infected cells and bind even more tightly to the adenovirus proteinase.

"This work should pave the way for the development of effective drugs against all types of adenovirus infections," Mangel said...

Scientists identify promising antiviral compounds

Abiraterone: Hint of considerable added benefit for patients with metastatic prostate cancer

In continuation of  my update on Abiraterone

Abiraterone acetate (abiraterone for short, trade name: Zytiga) has been approved in Germany since December 2012 for men with metastatic prostate cancer that is not responsive to hormone blockade, who only have mild symptoms or so far none at all, and in whom chemotherapy is not yet indicated. In an early benefit assessment pursuant to the "Act on the Reform of the Market for Medicinal Products" (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether abiraterone offers an added benefit compared with the present standard therapy....

Abiraterone: Hint of considerable added benefit for patients with metastatic prostate cancer