Friday, August 9, 2013

Necrostatin-1 counteracts aluminum's neurotoxic effects



we know that, Necrostatin-1 inhibits necroptosis, a non-apoptotic cell death pathway. Inhibits the loss of mitochondrial membrane potential in TNFα-treated Jurkat cells (EC50=490 nM). Does not inhibit FAS-induced apoptosis and has no effect on apoptotic morphology. It displays a pronounced protective effect in a mouse model of ischemic brain injury and inhibits myocardial cell death. Inhibits RIP1 kinase the key upstream kinase involved in the activation of necroptosis (EC50=180nM).


Ivestigators have linked aluminum accumulation in the brain as a possible contributing factor to neurodegenerative disorders such as Alzheimer's disease. A new study published in Restorative Neurology and Neuroscience sheds light on the mechanism underlying aluminum-induced neuronal cell death and identifies necrostatin-1 as a substance which counteracts several of aluminum's neurotoxic effects.


Acid reflux drug may cause heart disease, study suggests

In human tissue and mouse models, the researchers found PPIs (proton pump inhibitors) caused the constriction of blood vessels. If taken regularly, PPIs could lead to a variety of cardiovascular problems over time, including hypertension and a weakened heart. In the paper, the scientists call for a broad, large-scale study to determine whether PPIs are dangerous.
"The surprising effect that PPIs may impair vascular health needs further investigation," said John Cooke, M.D., Ph.D., the study's principal investigator. "Our work is consistent with previous reports that PPIs may increase the risk of a second heart attack in people that have been hospitalized with an acute coronary syndrome. Patients taking PPIs may wish to speak to their doctors about switching to another drug to protect their stomachs, if they are at risk for a heart attack."
Commonly used proton pump inhibitors in the United States are lansoprazole (below left) and omeprazole (below right), 

and these drugs are purchasable over the counter as brands or generics. The FDA estimates about 1 in 14 Americans has used them. In 2009, PPIs were the third-most taken type of drug in the U.S., accounting for $13 billion in sales. PPIs are used to treat a wide range of disorders, including gastroesophageal reflux disease, or GERD, infection by the ulcer-causing Helicobacter pylori, Zollinger-Ellison syndrome, and Barrett's esophagus.
Recent studies of proton pump inhibitors use by people who've already experienced severe cardiovascular events have raised concern about the anti-reflux drugs, at least for this subgroup of patients, said Cooke, chair of the Department of Cardiovascular Sciences and director of the Center for Cardiovascular Regeneration at Houston Methodist DeBakey Heart & Vascular Center.
PPIs are initially inert. After oral consumption, they are activated by specialized cells in the stomach. Once active, the molecules suppress the movement of protons into the intestine, which reduces the amount of acid present there and in the stomach.
In mouse models and cultures of human endothelial cells, Cooke and lead author Yohannes Ghebramariam, Ph.D., found that PPIs suppressed the enzyme DDAH, dimethylarginine dimethylaminohydrolase. That caused an increase in the blood levels of ADMA (asymmetric dimethylarginine), an important chemical messenger. They found ADMA in turn suppressed the production of another chemical messenger, nitric oxide, or NO, proven by 1998 Nobel Prize winners Furchgott, Ignarro, and Murad to impact cardiovascular function. Quantitative studies in mouse models showed animals fed PPIs were more likely than controls to have tense vascular tissue.
"We found that PPIs interfere with the ability of blood vessels to relax," said Ghebremariam, a Houston Methodist molecular biologist. "PPIs have this adverse effect by reducing the ability of human blood vessels to generate nitric oxide. Nitric oxide generated by the lining of the vessel is known to relax, and to protect, arteries and veins."
The researchers found PPIs led to an approximately 25 percent increase in ADMA in mouse and tissue cultures, and reduced the ability of mouse blood vessels to relax by over 30 percent on average.

Thursday, August 8, 2013

Phase III trial shows afatinib offers clinical benefit to patients with EGFR mutation positive NSCLC

We know that, Afatinib (INN; trade name Gilotrif, previously Tomtovok and Tovok) is an approved drug against non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim As of July 2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well asPhase II trials for prostate and head and neck cancer, and a Phase I glioma trial. Afatinib is a first-line treatment
.
In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug. Fall 2010 interim results suggested the drug extendedprogression-free survival threefold compared to placebo, but did not extend overall survival. In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.

Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib. Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.

Mechanism of action :: Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation TKIs like erlotinib or gefitinib, but also against those not sensitive to these standard therapies. Because of its additional activity against Her2, it is investigated for breast cancer as well as other EGFR and Her2 driven cancers.


FDA Approves Khedezla for Major Depressive Disorder

We know that, Desvenlafaxine (brand namePristiq), also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth (now part of Pfizer). Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (sold under the brand names Effexor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause


Wednesday, August 7, 2013

FDA Approves Gilotrif for Late Stage Non-Small Cell Lung Cancer

We know that, Afatinib, trade name Gilotrif, previously Tomtovok and Tovok is an approved drug against non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim. As of  2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well as Phase II trials for prostate and head and neck cancer, and a Phase I glioma trial. Afatinib is a first-line treatment.


Now FDA has approved...

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.”
In May, the FDA approved Tarceva (erlotinib) for first-line treatment of patients with NSCLC. Tarceva’s new indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic to identify patients with tumors having the EGFR gene mutations.
“The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health...
More ....





Tuesday, August 6, 2013

Compounds outsmart solid tumors' malfunctioning machinery


In continuation of my update on Rapamycin

"Allosteric regulators are better than proteasome-affecting agents used in clinics because they do not induce classical drug resistance," Dr. Gaczynska said. "They bind to sites on the proteasome molecule used by natural regulatory proteins. They are more specific and are not restricted to proteasome inhibition but can activate the proteasome under certain conditions."

The new strategy was serendipitously found during experiments with rapamycin, a drug that in a highly publicized study by the UT Health Science Center's Barshop Institute for Longevity and Aging Studies was found to extend life span in mice.

Potential
The Molecular Pharmacology report and follow-up studies describe the unexpected and highly desired effects that rapamycin and similar compounds elicit on the proteasome. Based on these studies, it would be possible to design a new line of proteasome regulators with anti-cancer properties, Drs. Osmulski and Gaczynska said.... 

Monday, August 5, 2013

Multiple sclerosis drug shows promise for preventing heart failure

A drug already approved to treat multiple sclerosis may also hold promise for treating cardiac hypertrophy, or thickening of the cardiac muscle-a disorder that often leads to heart failure, researchers at the University of Illinois at Chicago College of Medicine report. 


Using an experimental mouse model of cardiac hypertrophy, Solaro and his team found that FTY-720 (Fingolimod, see structure) significantly reduced heart mass; lessened fibrosis, or stiffening of the heart muscle; and improved overall cardiac function in the mice that received the drug.

The researchers also showed that the drug inhibits expression of several genes involved in cardiac hypertrophy.

"We saw that FTY-720 blocked the activity of a protein we know is involved in causing heart-cell thickening," said Solaro. When that protein is blocked, he said, collagen and other proteins involved in heart-cell thickening are also down-regulated.

Collagen, a fibrous protein found between heart cells, causes the heart muscle to become stiff. Collagen is often overabundant in people with cardiac hypertrophy.

"When the heart muscle is stiff, it actually takes effort to relax the heart and allow blood to flow into the ventricles, so this is another way this disease causes the heart to work harder than it should have to," Solaro said.

"FTY-720 is a potential therapy to treat this disease and prevent heart failure for people where the disease is acquired through high blood pressure, and possibly inherited hypertrophy as well," he said.



Friday, August 2, 2013

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....

Thursday, August 1, 2013

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.


Wednesday, July 31, 2013

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."

Tuesday, July 30, 2013

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).

Monday, July 29, 2013

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.....


Friday, July 26, 2013

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 CRFurotensin Isauvagineurocortin 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.

Thursday, July 25, 2013