New version of common antibiotic could eliminate risk of hearing loss

"All I remember is coming out of treatment not being able to hear anything," said Bryce, now a healthy 14-year-old living in Arizona. "I asked my mom, 'Why have all the people stopped talking?'" He was 90 percent deaf.

"The loss has been devastating," said his father, Bart Faber. "But not as devastating as losing him would have been."

Treatment with aminoglycosides, the most commonly used class of antibiotics worldwide, is often a lifesaving necessity. But an estimated 20-60 percent of all patients who receive these antibiotics suffer partial or complete hearing loss.

Now, in a study that will be published online Jan. 2 in the Journal of Clinical Investigation, researchers at the Stanford University School of Medicine report that they have developed a modified version of an aminoglycoside that works effectively in mice without the risk of causing deafness or kidney damage, another common side effect.

The researchers hope to test versions of the modified antibiotic in humans as soon as possible.

"If we can eventually prevent people from going deaf from taking these antibiotics, in my mind, we will have been successful," said Anthony Ricci, PhD, professor of otolaryngology-head and neck surgery and co-senior author of the study. "Our goal is to replace the existing aminoglycosides with ones that aren't toxic."

Four years in the making

It took the scientists four years of research to produce 5 grams of the newly patented antibiotic, N1MS, which is derived from sisomicin, a type of aminoglycoside.

N1MS cured urinary tract infection in mice just as well as sisomcicin, but did not cause deafness, study results show. The study presents a promising new approach to generating a new class of novel, nontoxic antibiotics, Ricci said.

The two senior authors -- Ricci and Alan Cheng, MD, associate professor of otolaryngology-head and neck surgery -- joined forces in 2007 to explore the idea of creating new and improved versions of these antibiotics based on a simple yet groundbreaking idea born of Ricci's basic science research into the biophysics of how hearing works within the inner ear.

"It's a nice example of how basic science research is directly translatable into clinical applications," said Ricci.

Ricci is an expert on the process by which sound waves open ion channels within the sensory hair cells of the inner ear, allowing their conversion to electrical signals that eventually reach the brain.

Because aminoglycosides cause deafness by killing these nonregenerating hair cells, Ricci postulated, why not simply make the drug molecules unable to enter the cells' channels?

The idea made sense to Cheng.

"As a clinician-scientist, I treat kids with hearing loss," Cheng said. "When a drug causes hearing loss it is devastating, and it's especially disturbing when this happens to a young child as they rely on hearing to acquire speech.

"When I came to Stanford seven years ago from the University of Washington, I was exploring the angle that maybe we could add drugs to protect the ear from toxicity. Tony brought up this new idea: Why don't we just not let the drug get in? Great idea, I thought. When do we start to work?"

A potent antibiotic

For 20 years, and despite newer, alternative antibiotics, aminoglycosides have remained the mainstay treatment worldwide for many bacterial diseases, including pneumonia, peritonitis and sepsis. They also are often used when other antibiotics have failed to treat infections of unknown origins.

Their popularity is due, in part, to their low cost, lack of need for refrigeration and effectiveness at treating bacterial infections at a time when the declining potency of antibiotics is a major public health concern. They are frequently used in neonatal intensive care units to battle infections, or even the threat of infections, which pose a life-threatening risk for babies. Exactly how many premature babies suffer hearing loss as a side effect of treatment with the drug is unknown, Ricci said.

"The toxicity of these drugs is something we accept as a necessary evil," said Daria Mochly-Rosen, PhD, director of SPARK, a program at Stanford that assists scientists in moving their discoveries from bench to bedside.

Ref : http://dx.doi.org/10.1172/JCI77424

New version of common antibiotic could eliminate risk of hearing loss  

New treatment approach may improve survival rates for certain patients with stage 4 lung cancer

A clinical trial that combined stereotactic body radiation therapy with a specific chemotherapy regimen more than doubled survival rates for certain stage 4 lung cancer patients, UT Southwestern Medical Center cancer researchers report.

The combination of the chemotherapy regimen, erlotinib, with stereotactic body radiation therapy, known as SBRT, improved overall survival time to 20 months compared to historic 6- to 9- month survival times among erlotinib-only treated patients. The combination improved progression free survival - the time without the reappearance of cancer − from the historical two to four months to 14.7 months for similarly selected lung cancer patients.

"Our approach dramatically changed the pattern of relapse. We saw a shift in failure from existing, local sites to new, distant sites," said senior author Dr. Robert Timmerman, Director of the Annette Simmons Stereotactic Treatment Center, and Vice Chairman of Radiation Oncology at UT Southwestern. "This shift resulted in a surprisingly long remission from the reappearance of cancer in treated patients."

New treatment approach may improve survival rates for certain patients with stage 4 lung cancer

Honey offers new approach to fighting antibiotic resistance ............

In continuation of my update on Honey..

Honey, that delectable condiment for breads and fruits, could be one sweet solution to the serious, ever-growing problem of bacterial resistance to antibiotics, researchers said in Dallas* today. Medical professionals sometimes use honey successfully as a topical dressing, but it could play a larger role in fighting infections, the researchers predicted.

"The unique property of honey lies in its ability to fight infection on multiple levels, making it more difficult for bacteria to develop resistance," said study leader Susan M. Meschwitz, Ph.D. That is, it uses a combination of weapons, including hydrogen peroxide, acidity, osmotic effect, high sugar concentration and polyphenols -- all of which actively kill bacterial cells, she explained. The osmotic effect, which is the result of the high sugar concentration in honey, draws water from the bacterial cells, dehydrating and killing them.

In addition, several studies have shown that honey inhibits the formation of biofilms, or communities of slimy disease-causing bacteria, she said. "Honey may also disrupt quorum sensing, which weakens bacterial virulence, rendering the bacteria more susceptible to conventional antibiotics," Meschwitz said. Quorum sensing is the way bacteria communicate with one another, and may be involved in the formation of biofilms. In certain bacteria, this communication system also controls the release of toxins, which affects the bacteria's pathogenicity, or their ability to cause disease.

Meschwitz, who is with Salve Regina University in Newport, R.I., said another advantage of honey is that unlike conventional antibiotics, it doesn't target the essential growth processes of bacteria. The problem with this type of targeting, which is the basis of conventional antibiotics, is that it results in the bacteria building up resistance to the drugs.

Honey is effective because it is filled with healthful polyphenols, or antioxidants, she said. These include the phenolic acids, caffeic acid, p-coumaric acid and ellagic acid, as well as many flavonoids. "Several studies have demonstrated a correlation between the non-peroxide antimicrobial and antioxidant activities of honey and the presence of honey phenolics," she added. A large number of laboratory and limited clinical studies have confirmed the broad-spectrum antibacterial, antifungal and antiviral properties of honey, according to Meschwitz.

She said that her team also is finding that honey has antioxidant properties and is an effective antibacterial. "We have run standard antioxidant tests on honey to measure the level of antioxidant activity," she explained. "We have separated and identified the various antioxidant polyphenol compounds. In our antibacterial studies, we have been testing honey's activity against E. coli, Staphylococcus aureus and Pseudomonas aeruginosa, among others."

Honey offers new approach to fighting antibiotic resistance  

Newron, Zambon announce re-submission of safinamide NDA to FDA

In continuation of my update on safinamide 

Newron Pharmaceuticals S.p.A. ("Newron"), a research and development company focused on novel CNS and pain therapies, and its commercial and development partner Zambon S.p.A., an international pharmaceutical company, announced  that the NDA for safinamide has been re-submitted to the US FDA. This follows the announcement last week that the CHMP has given a positive opinion on safinamide for Europe.

The submission covers the indications "safinamide as add-on therapy to a stable dose of a single dopamine agonist" in early Parkinson's disease patients and "safinamide as add-on therapy to levodopa alone or in combination with other Parkinson's disease treatments" in mid-to late stage Parkinson's disease patients.

The first submission of safinamide to the US FDA was made in May 2014. On review, the FDA issued a Refusal to File (RTF) letter based on organizational and navigational problems, largely due relating to the hyperlinking of tables, folders and the organization of the table of contents in the submission.

Ravi Anand, Newron's CMO, stated: "Newron has been in frequent contact with the FDA to propose solutions to the technical issues and obtain their concurrence with the proposals. These discussions lead Newron to conclude that the RTF issues have been addressed in this submission."

Newron, Zambon announce re-submission of safinamide NDA to FDA

Can-Fite BioPharma completes RA Phase III study of lead drug candidate CF101

Can-Fite BioPharma Ltd.  a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, announced today that it completed the design of the Rheumatoid Arthritis (RA) Phase III study of its lead drug candidate CF101. Dr. M. Silverman, Can-Fite Medical Director, and Dr. Lee Simon, a key opinion leader in the field of autoimmune inflammatory diseases, designed the Phase III clinical study.

The Phase III study will be a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that will investigate the efficacy and safety of daily CF101 administered orally as a monotherapy for 12 weeks to patients with active RA. The study will have three arms, a 2 mg CF101 dose, a 3mg CF101 dose and placebo, given orally twice daily in the form of tablets. Approximately 300 patients are expected to be enrolled in the study, where sample size for each treatment group will be approximately 100 patients and will provide a statistical power of at least 90%. The study primary end point will be ACR 20 response at Week 12. The A3 adenosine receptor biomarker will be evaluated prior to treatment and its correlation to patients' response to the drug will be analyzed upon study conclusion.

Can-Fite BioPharma completes RA Phase III study of lead drug candidate CF101

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

In continuation of my update on Bedaquiline

While an effective treatment is available for combating multidrug-resistant tuberculosis, it carries serious side effects for patients. New research conducted at the Center for Tuberculosis Research at the Johns Hopkins University School of Medicine shows that lower doses of the toxic drug bedaquiline — given together with verapamil, a medication that's used to treat various heart conditions — can lead to the same antibacterial effects as higher toxic doses of bedaquiline. The combination of the two drugs could potentially shorten treatment time, reduce the side effects of bedaquiline and improve patient outcomes for those suffering from TB.

The study will be published in the January 2014 issue of Antimicrobial Agents and Chemotherapy. The lead author is William Bishai, M.D., Ph.D., co-director of the Center for Tuberculosis Research.

"Using a mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses," says Shashank Gupta, Ph.D., a research fellow at Johns Hopkins. "A lower dose of bedaquiline will cause no or less severe side effects."

Two years ago, bedaquiline became the first drug in the last four decades to be approved by the U.S. Food and Drug Administration for the treatment of multidrug-resistant TB. The drug works by inhibiting an enzyme used by Mycobacterium tuberculosis to replicate and spread throughout the body. While it can be a lifesaving therapy against one of the world's deadliest diseases, bedaquiline can also cause serious side effects in the heart and liver. Therefore, strategies to reduce the dose of bedaquiline while retaining its antibacterial activity would provide significant benefits to patients.

"Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve multidrug-resistant TB treatment outcomes," says Gupta.

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

FDA approves Myriad’s BRACAnalysis CDx for use with ovarian cancer drug

In continuation of my update on Olaparib

Myriad Genetics, Inc.    announced that it has received approval from the U.S. Food and Drug Administration (FDA) for BRACAnalysis CDx to be used as the only companion diagnostic in conjunction with AstraZeneca’s drug Lynparza™ (olaparib). Lynparza is the first poly ADP-ribose polymerase (PARP) inhibitor for patients with germline mutations in BRCA1/2 advanced ovarian cancer who have had three or more lines of chemotherapy. BRACAnalysis CDx is Myriad’s first FDA-approved companion diagnostic for use with a novel PARP inhibitor.

FDA approves Myriad’s BRACAnalysis CDx for use with ovarian cancer drug

Final Phase 1 data of zoptarelin doxorubicin Phase 1/2 trial published in Clinical Cancer Research

Aeterna Zentaris Inc. (NASDAQ: AEZS, TSX: AEZ) (the "Company")  announced that an article on final data for the Phase 1 portion of the ongoing Phase 1/2 trial in prostate cancer with zoptarelin doxorubicin (formerly AEZS-108), a hybrid molecule composed of a synthetic peptide carrier and a well-known chemotherapy agent, doxorubicin, has been published in the December issue of Clinical Cancer Research. The article outlines data previously disclosed in June 2013 at the American Society of Clinical Oncology's ("ASCO") Annual Meeting, which demonstrated the compound's safety profile and promising anti-tumor activity in heavily pre‑treated men with castration- and taxane-resistant prostate cancer. These results led to the current investigator-driven Phase 2 portion in this same indication under the supervision of lead investigator, Jacek Pinski, MD, PhD, of the USC Norris Comprehensive Cancer Center. Titled, "Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer", Liu SV, Tsao-Wei DD, Xiong S, Groshen S, Dorff TB, Quinn DI, Tai YC, Engel J, Hawes D, Schally AV, Pinski J., the article is available at this link: Clin Cancer Res.

Final Phase 1 data of zoptarelin doxorubicin Phase 1/2 trial published in Clinical Cancer Research

Broccoli can help reduce HGPS-related defects

In continuation of my update on broccoli...

Children who suffer from Hutchinson-Gilford Progeria syndrome age prematurely due to a defective protein in their cells. Scientists at Technische Universität München have now identified another important pathological factor: the system responsible for removing cellular debris and for breaking down defective proteins operates at lower levels in HGPS cells than in normal cells. The researchers have succeeded in reactivating protein breakdown in HGPS cells and thus reducing disease-related defects by using a substance from broccoli.

Most Hutchinson-Gilford Progeria Syndrome (HGPS) patients carry a mutation that produces a defective form of the protein lamin A. This defective protein is referred to as progerin. Normal lamin A is a key component of the matrix surrounding the DNA in the cell nucleus and plays a role in gene expression. By contrast, the defective form, progerin, is not functional but is nevertheless continuously synthesized. The result is that progerin accumulates in the nucleus and causes the cell to "age". Consequently, HGPS patients develop classic diseases of old age such as atherosclerosis, osteoporosis, heart attacks and strokes. The disease is therefore regarded as a possible model system for the natural aging process in cells.

A window on the cell nucleus

In order to find out which specific metabolic pathways are affected by the mutation and the defective protein, Prof. Karima Djabali and her team from the TUM School of Medicine and the Institute for Medical Engineering conducted a comparative study of diseased and healthy tissue cells in which they investigated the composition of proteins in the cell nuclei and looked for differences.

Broccoli can help reduce HGPS-related defects

Ganciclovir drug resistance may occur more frequently in cystic fibrosis patients

A drug called ganciclovir is given to lung transplant patients to protect against a life-threatening virus that is common after transplantation.

Ganciclovir reduces mortality due to the virus from 34 percent to between 3 and 6 percent. But between 5 percent and 10 percent of patients infected with the virus have strains that are resistant to the drug.

A Loyola University Medical Center study found that such resistance may occur more frequently in cystic fibrosis patients. These patients were found to have insufficient levels of the drug in their bloodstream, enabling the virus to continually replicate. This in turn may increase the chance that mutations will occur and result in drug resistance.

The study suggests that cystic fibrosis patients should be monitored to ensure there are therapeutic levels of ganciclovir in their bodies, said James Gagermeier, MD, first author of the study. The study is published online ahead of print in the journal Transplant Infectious Disease.

Ganciclovir drug resistance may occur more frequently in cystic fibrosis patients

Palatin begins bremelanotide phase 3 study for treatment of female sexual dysfunction

Palatin Technologies, Inc. (NYSE MKT: PTN), a biopharmaceutical company developing targeted, receptor-specific peptide therapeutics for the treatment of diseases with significant unmet medical needs and commercial potential, today announced that it has started its bremelanotide pivotal registration program. The Company has initiated its phase 3 reconnect study in the United States for the treatment of female sexual dysfunction (FSD).

"We are pleased to achieve this major milestone in the bremelanotide program with the initiation of our phase 3 reconnect study in the U.S," stated Carl Spana, Ph.D., President and CEO of Palatin. "This is a key step in our global strategy to bring bremelanotide to market for the millions of women who have FSD and are seeking a safe and effective treatment." Dr. Spana further stated that, "Our recent $30 million financing has provided the financial resources to start the bremelanotide phase 3 pivotal registration program and timing flexibility regarding partnering for the U.S. and other non-European territories."

Palatin begins bremelanotide phase 3 study for treatment of female sexual dysfunction

Can-Fite BioPharma begins dosing in CF102 Phase II liver cancer trial

Can-Fite BioPharma Ltd. , a biotechnology company advancing a pipeline of proprietary small molecule drugs that address cancer and inflammatory diseases, today announced that it has dosed the first patient in a Phase II trial for the treatment of hepatocellular carcinoma (HCC), the most common form of liver cancer.

The Phase II randomized, double-blind, placebo controlled trial is to be conducted in the U.S., Europe and Israel with an estimated 78 patients to be enrolled. CF 102 is being evaluated for efficacy and safety as a second-line treatment for advanced HCC in subjects with Child-Pugh B who failed Nexavar as a first line treatment. The first patient was dosed at the study's Israeli site, the Rabin Medical Center. The primary endpoint of the study is overall patient survival.

Can-Fite BioPharma begins dosing in CF102 Phase II liver cancer trial

Intriguing small molecule directs activity of key ‘clock proteins’

In research published in Nature Communications, Thomas Burris, Ph.D., chair of pharmacological and physiological science at Saint Louis University, reports intriguing findings about a small molecule that directs the activity of key "clock proteins," offering the potential to manage circadian rhythm and treat problems that are associated with its dysfunction, like sleep and anxiety disorders.

 

Circadian rhythm refers to biological processes that cycle every 24 hours. In mammals, the internal clock that maintains circadian rhythm is essential for normal physiological functions. The rhythms can, however, be disrupted, and dysregulation of circadian rhythm is associated with many disorders, including metabolic disease and neuropsychiatric disorders including bipolar disorder, anxiety, depression, schizophrenia and sleep disorders.

Burris and his colleagues examined compounds that target a protein called REV-ERB, which appears to play a key role in regulating mammals' internal clocks.

"It has been suggested that REV-ERB is a core component of our clock," said Burris. "Mice without it are arrhythmic. This study demonstrated that when we give mice a synthetic compound that turns REV-ERB on, it altered their circadian rhythm."

The team examined effects of the REV-ERB drug on patterns of sleep and wakefulness and found that the compound increases wakefulness, reduces REM and slow-wave sleep, and, notably, decreases anxiety.

This is an interesting finding because it is unusual. Frequently, drugs that increase arousal (wakefulness) also increase anxiety (ex. cocaine, amphetamines). And, vice versa: Drugs that decrease anxiety also decrease arousal (ex. benzodiazepines and ethanol). An exception to this common pattern is nicotine.

Intriguing small molecule directs activity of key ‘clock proteins’

Actavis receives complete response letter for nebivolol/valsartan FDC for treatment of hypertension

In continuation of my  update on Valsartan

Actavis plc , confirmed that the Company has received a complete response letter from the U.S. Food and Drug Administration (FDA) for its New Drug Application (NDA) for the fixed-dose combination (FDC) of nebivolol (below structure)  and valsartan for the treatment of hypertension.

"Although we are disappointed in the receipt of a complete response letter, Actavis remains committed to bringing treatments to market that address the significant public health issue of cardiovascular disease," said David Nicholson, Senior Vice President, Actavis Global Brands R&D. "Bystolic is a safe and effective option that is commonly used in combination with other antihypertensive medications to help patients reach blood pressure treatment goals. We will review the complete response and determine the appropriate next steps."

Actavis receives complete response letter for nebivolol/valsartan FDC for treatment of hypertension

Mirati begins dosage in MGCD265 Phase 1b clinical trial for NSCLC

Mirati Therapeutics, Inc. (NASDAQ: MRTX) today announced that the first patient with Non-Small Cell Lung Cancer (NSCLC) has been dosed in a Phase 1b clinical trial of MGCD265 in selected patients exhibiting genetic alterations of MET or Axl. In this segment of the study, one of the expansion cohorts will enroll patients with NSCLC and another will enroll patients with other solid tumors. Both cohorts will enroll only those patients that have specific MET driver mutations including MET gene point mutations, gene amplification, and MET or Axl gene rearrangements.

"In the dose escalation phase of this trial, we identified an optimal dose that achieved serum levels that we believe will result in greater than 90% inhibition of MET and Axl," said Charles M. Baum, M.D., Ph.D., president and CEO of Mirati. "We are focused on patients whose tumors harbor the specific MET and Axl genetic alterations that MGCD265 is designed to treat. By selecting and treating only those patients who carry the targeted mutations, there is strong rationale that we'll see proof of concept based on a high overall response rate in early 2015 that supports accelerated drug development."

Mirati begins dosage in MGCD265 Phase 1b clinical trial for NSCLC

FDA approves Namzaric drug for treatment of moderate to severe Alzheimer's disease

FDA approves Namzaric drug for treatment of moderate to severe Alzheimer's disease

Pre-clinical studies confirm TRXE-009 as new potential treatment for melanoma

Novogen Limited (ASX:NRT; NASDAQ: NVGN), Australian/US biotechnology company, announces that it has confirmed that its lead candidate product, TRXE-009, originally developed for the treatment of brain cancers, has been shown in pre-clinical studies also to be highly active against melanoma.

The Company believes this is an important breakthrough discovery for two reasons. The first is that it confirms that TRXE-009 is an important new potential treatment for melanoma, including for the treatment of secondary brain cancers due to melanoma, for which there currently are no effective therapies. The second is that it offers evidence for the first time of an hypothesized link between brain cancer and melanoma.

The link has long been considered a possibility because nerve cells and melanocytes (the melanin pigment-bearing cells in skin that lead to melanoma) have a common origin in the embryo known as the neural crest. This primitive tissue gives rise to the neural cells that go on to form the brain, spinal cord, and peripheral nerves, as well as cells that form the structures of the skull; melanocytes also come from this embryonic tissue. Up till now, no functional link has been found between brain cells and melanocytes, or between brain cancer and melanoma. TRXE-009 is the first compound to demonstrate the possibility of a common link, suggesting that is the first drug with the ability to identify cancers arising in cells that have the neural crest as their common origin.

Pre-clinical studies confirm TRXE-009 as new potential treatment for melanoma

Isis Pharmaceuticals begins ISIS-DMPK Rx clinical study in DM1 patients

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced  that it has initiated a study for ISIS-DMPKRx in patients with Myotonic Dystrophy Type 1 (DM1). DM1 is a rare genetic neuromuscular disease caused by the production of toxic dystrophia myotonica-protein kinase (DMPK) RNA in cells. ISIS-DMPKRx is specifically designed to reduce toxic DMPK RNA.

"The Myotonic Dystrophy Foundation is pleased that Isis is advancing to the next phase of clinical trials for ISIS-DMPKRx," said Molly White, executive director of the Myotonic Dystrophy Foundation. "Myotonic Dystrophy, the most common form of muscular dystrophy, is a devastating disease with no therapeutic option. Myotonic dystrophy research has accelerated significantly in the last 10 years, helping bring about the innovative science behind ISIS-DMPKRx, a drug that specifically targets the genetic defect that causes myotonic dystrophy type 1. We applaud Isis for investing in and leading drug development efforts for myotonic dystrophy type 1, and we appreciate the commitment Isis Pharmaceuticals has made to improve the lives of patients in our community."

"We have an innovative and productive partnership with Biogen Idec in developing drugs to treat severe and rare diseases, like DM1. In just under two and a half years, we have been able to discover and complete early development on ISIS-DMPKRx, which includes completing a Phase 1 single ascending-dose study in healthy volunteers. Today we advance this program into patients," said B. Lynne Parshall, chief operating officer at Isis. "The speed at which we have advanced ISIS-DMPKRx highlights the productive and collaborative nature of our partnership."

Isis Pharmaceuticals begins ISIS-DMPK Rx clinical study in DM1 patients

Researchers identify 53 existing drugs that may block Ebola virus from entering human cells

Researchers found 53 existing drugs that may keep the Ebola virus from entering human cells, a key step in the process of infection, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and the National Institutes of Health (NIH), and published today in the Nature Press journal Emerging Microbes and Infections.

Among the better known drug types shown to hinder infection by an Ebola virus model: several cancer drugs, antihistamines and antibiotics. Among the most effective at keeping the virus out of human cells were microtubule inhibitors used to treat cancer.

"In light of the historic and devastating outbreak of Ebola virus disease, there is an urgent need to rapidly develop useful treatments against Ebola infection, and our study results argue that repurposing existing drugs may be among the fastest ways to achieve this," said lead author Adolfo García-Sastre, PhD, Director of the Global Health and Emerging Pathogens Institute within the Icahn School of Medicine at Mount Sinai. "Many of the compounds identified in this study promise to become lead compounds in near-future drug development efforts studies targeting this virus," said Dr. García-Sastre, also the Fishberg Chair and Professor of Medicine (Infectious Diseases) within the School.

A few are listed below...

Ref : http://www.nature.com/emi/journal/v3/n12/full/emi201488a.html

Nocodazole (IC₅₀=0.4 µM), Toremifene (0.55 µM), Tamoxifen (0.76 µM), Raloxifene 1.84 (1.53 µM), Cepharanthine (1.53 µM), Clomiphene (1.72 µM), Dronedarone (2.2 µM), Amodiaquine (4.43 µM), Imipramine (13.7 µM), Chloroquine (15.3 µM), and Nilotinib (15.3 µM).

Researchers identify 53 existing drugs that may block Ebola virus from entering human cells

Study shows how cannabidiol works within cells

A team of Stony Brook University researchers have identified fatty acid binding proteins (FABPs) as intracellular transporters for two ingredients in marijuana, THC and CBD (cannabidiol). The finding, published early online in the Journal of Biological Chemistry, is significant because it helps explain how CBD works within the cells. Recent clinical findings have shown that CBD may help reduce seizures and could be a potential new medicine to treat pediatric treatment-resistant epilepsy.

CBD differs from THC in that it is not psychoactive and does not bind to cannabinoid receptors. Some children who are resistant to conventional antiepileptic drugs have been reported to show improvement with oral CBD treatment. The Stony Brook research team found that three brain FABPs carry THC and CBD from the cell membrane to the interior of the cell. This action enabled them to conduct experiments inhibiting FABPs and thereby reducing anandamide breakdown inside the cells.

"Anandamide, an endocannabinoid, has been shown to have neuroprotective effects against seizures in basic research studies and this may turn out to be a key mechanism of seizure control," explained Dale Deutsch, PhD, Professor of Biochemistry and Cell Biology and a faculty member of the Institute of Chemical Biology and Drug Discovery at Stony Brook University. "Therefore by CBD inhibiting FABPs, we could potentially raise the levels of anandamide in the brain's synapses."

Study shows how cannabidiol works within cells

Jazz Pharmaceuticals to present defibrotide results for hepatic VOD at BMT Tandem meetings

Jazz Pharmaceuticals plc (Nasdaq: JAZZ) announced today that researchers will present data on the use of defibrotide, an investigational medicine being studied in the United States (U.S.) for the treatment of hepatic veno-occlusive disease (VOD), a rare, potentially life-threatening, early complication in patients undergoing hematopoietic stem-cell transplantation (HSCT) therapy. The three presentations include an update from an ongoing treatment investigational new drug (T-IND) study in the U.S., as well as updates from a number needed to treat (NNT, an epidemiological measure of effectiveness) analysis from a historically controlled pivotal Phase 3 trial in patients undergoing HSCT therapy, and from an international defibrotide compassionate use program.

Data from the three defibrotide studies will be presented today in an oral abstract session at the 2015 BMT (Bone Marrow Transplantation) Tandem meetings, the combined annual meetings of the American Society of Blood and Marrow Transplantation (ASBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR), in San Diego, California. BMT Tandem is one of the largest international forums dedicated specifically to HSCT.

"VOD is a potentially life-threatening complication in patients undergoing HSCT therapy, and there are currently no approved therapies for VOD in the U.S," said Jeffrey Tobias, M.D., executive vice president and chief medical officer of Jazz Pharmaceuticals. "The data presented at the BMT Tandem meetings build upon existing evidence showing that, when recognized and diagnosed, severe VOD may be effectively treated with defibrotide. The data also provide additional information on defibrotide's efficacy and safety profile in important subgroups of patients such as children, adults, and allograft and autograft recipients."

Jazz Pharmaceuticals to present defibrotide results for hepatic VOD at BMT Tandem meetings

'Mad Cow' discovery points to possible neuron killing mechanism behind alzheimer’s and parkinson’s diseases

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time discovered a killing mechanism that could underpin a range of the most intractable neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS.

The new study, published recently in the journal Brain, revealed the mechanism of toxicity of a misfolded form of the protein that underlies prion diseases, such as bovine spongiform encephalopathy (“mad cow disease”) and its human equivalent, Creutzfeldt-Jakob disease.

Our study reveals a novel mechanism of neuronal death involved in a neurodegenerative protein-misfolding disease,” said Corinne Lasmézas, a TSRI professor who led the study. “Importantly, the death of these cells is preventable. In our study, ailing neurons in culture and in an animal model were completely rescued by treatment, despite the continued presence of the toxic misfolded protein. This work suggests treatment strategies for prion diseases—and possibly other protein misfolding diseases such as Alzheimer’s.

'Mad Cow' discovery points to possible neuron killing mechanism behind alzheimer’s and parkinson’s diseases

Diabetes drug can boost efficacy of TB medication without causing drug resistance

In continuation of my update on Metformin

A more effective treatment for tuberculosis (TB) could soon be available as scientists have discovered that Metformin (MET), a drug for treating diabetes, can also be used to boost the efficacy of TB medication without inducing drug resistance.

This discovery was made by a team of international scientists led by the Singapore Immunology Network (SIgN), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore.

TB is an air-borne infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb), which often infects the lungs. Even though drugs are available to treat the disease, TB continues to be a major threat to public health, killing close to 1.5 million people every year .

Conventional drugs used to treat TB usually adopt a pathogen-targeted strategy which attacks and kills bacteria directly. This approach has caused Mtb strains to acquire drug resistance, making existing treatments become increasingly ineffective and resulting in a pressing need to design new therapeutic strategies for the disease.

MET as an adjunct treatment for TB

The team of scientists led by SIgN began searching for drugs that could control Mtb replication indirectly. They screened FDA-approved drugs and identified MET, an old anti-diabetic drug that could defend Mtb invasion without targeting the bacteria directly. Instead, MET targets the host cells to trigger the production of a chemical which then damages Mtb and stops its replication. Such indirect, host-targeted approach is less likely to engender drug resistance. The team also discovered that MET improves the efficacy of conventional anti-TB drugs when used in combination with them.

The scientists then validated the findings with patient data provided by the Tuberculosis Clinical Unit at the Tan Tock Seng Hospital, and consequently verified that the use of MET is indeed associated with improved TB control and decreased disease severity. This anti-diabetic drug is therefore a promising adjunctive therapy that could enhance the effectiveness of existing TB treatments. As it is a drug that is currently in use, another benefit of using MET as an adjunct treatment for TB is that it is likely to shorten the time required for clinical trials.

Diabetes drug can boost efficacy of TB medication without causing drug resistance

Study: Low glycemic diet does not improve insulin sensitivity or cardiovascular risk factors

Study: Low glycemic diet does not improve insulin sensitivity or cardiovascular risk factors

FL118 agent shows efficacy as personalized, targeted therapy for certain cancer tumors

A team led by Fengzhi Li, PhD, and Xinjiang Wang, PhD, of Roswell Park Cancer Institute (RPCI) has reported new findings regarding therapeutic targets of the novel anticancer agent FL118. Previous studies from these researchers have showed that FL118 induces cancer cell death, or apoptosis, by inhibiting expression of multiple cell-survival proteins (survivin, Mcl-1, XIAP or cIAP2). Study results published in the peer-reviewed American Association for Cancer Research journal Cancer Research  showed that FL118 can also activate   the p53 tumor-suppressor pathway in cancer cells, encouraging cell senescence,    or aging. In both processes, FL118 demonstrates potent antitumor efficacy,   suggesting additional applications as a personalized, targeted therapy for certain cancer tumors.

In a study of preclinical models of colorectal cancer, the researchers identified an underlying mechanism for the activation of p53 by FL118. The agent activates the p53 tumor-suppressor protein largely independent of ataxia telangiectasia mutated (ATM)-dependent DNA damage-mediated p53 activation. ATM-dependent activation of p53 is usually induced by many — if not all  types of DNA-damage drugs, including camptothecin compounds such as irinotecan and topotecan,  leading  the authors  to  conclude  that  FL118's mechanisms of action are distinct among camptothecin analogues.

"While FL118 is an analogue of irinotecan and topotecan, two FDA-approved cancer drugs that are also based on the naturally occurring compound camptothecin, our findings add further evidence that FL118 has novel mechanisms of action that may make it especially potent against solid tumors and especially effective as a well-tolerated, targeted therapy," said Dr. Li, an Associate Professor of Oncology in the Department of Pharmacology and Therapeutics.

FL118 agent shows efficacy as personalized, targeted therapy for certain cancer tumors

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

In continuation of my update on cisplatin and 5-fluorouracil derivative S-1v

Research suggests that treatment with cisplatin plus S-1 together with thoracic radiotherapy is relatively efficacious and tolerable in patients with locally advanced non-small-cell lung cancer (NSCLC).

Although cisplatin-based chemotherapy with thoracic radiotherapy is a standard treatment for unresectable, locally advanced NSCLC, the outcomes are not satisfactory, explain Katsuyuki Hotta, from Okayama University Hospital in Japan, and colleagues. They investigated the effect of adding the 5-fluorouracil derivative S-1 to the standard treatment in a phase II trial, the primary endpoint of which was the response rate.

A total of 48 patients with stage III NSCLC received cisplatin plus S-1 (at a dose of 40 mg/m2 twice daily from days 1–14 and 29–42 of treatment) with concurrent thoracic irradiation, of whom 37 had a partial response, giving an overall response rate (ORR) of 77%.

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

First-line dacomitinib may improve advanced NSCLC survival

 

Preliminary research suggests that the second-generation tyrosine kinase inhibitor (TKI) dacomitinib (see right structure)may improve progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

Noting that the majority of patients develop resistance to the first-generation TKIs, such as gefitinib and erlotinib (below structures from left and right side respectively), Pasi Jänne (Dana Farber Cancer Institute, Boston, Massachusetts, USA) and co-workers explain that alternative agents are needed to improve patient outcomes.

 

The open-label, phase II trial included 89 treatment-naïve patients with stage IIIB or IV NSCLC who were selected for dacomitinib once-daily treatment on the basis of clinical markers (never or former light smokers) or molecular markers (absence of KRASmutation in non-Asian patients or EGFR mutation).

First-line dacomitinib may improve advanced NSCLC survival

Isis announces top-line results from ISIS-PTP1B Rx Phase 2 study in type 2 diabetes patients

Isis announces top-line results from ISIS-PTP1B Rx Phase 2 study in type 2 diabetes patients

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

In continuation of my update on daclatasvir 

The drug daclatasvir (trade name Daklinza) has been available since August 2014 for the treatment of adults with chronic hepatitis C (CHC) infection. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether this new drug offers an added benefit over the appropriate comparator therapy.

The drug manufacturer presented data for patients without cirrhosis of the liver who are infected with hepatitis C virus (HCV) genotype 1, and for patients with HCV genotype 4. However, these data are unsuitable in various aspects to prove an added benefit.

The manufacturer dossier contained no data at all for three further patient groups with HCV genotype 1 infection (pretreated patients, untreated patients with cirrhosis of the liver, and patients with HIV coinfection) as well as for patients with HCV genotype 3 (with compensated cirrhosis and/or treatment-experienced).

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

Penn researchers find effective way to inhibit inflammatory response during kidney dialysis

Frequent kidney dialysis is essential for the approximately 350,000 end-stage renal disease (ESRD) patients in the United States. But it can also cause systemic inflammation, leading to complications such as cardiovascular disease and anemia, and patients who rely on the therapy have a five-year survival rate of only 35 percent. Such inflammation can be triggered when the complement cascade, part of the body's innate immune system, is inadvertently activated by modern polymer-based dialysis blood filters. New work by Penn researchers has found an effective way to avoid these problems by temporarily suppressing complement during dialysis. Their work appears online in Immunobiology ahead of print.

Over the past several years, lead author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine, Perelman School of Medicine at the University of Pennsylvania, and his colleagues have developed small molecule versions of the drug compstatin, which inhibits a component of the complement immune response called C3. Lambris explains that this next-generation compound, called Cp40, "is a small peptide similar to cyclosporine in many aspects, however it uses a different mechanism of action."

Previous studies by Lambris and his team, in which modern polymer-based hemodialysis filters were perfused with human blood, showed significant complement activation and an increase in inflammatory biomarkers. This response could be suppressed using compstatin, suggesting that it might be used in dialysis to decrease the inflammatory response side effect.

The new study took place in non-human primates to validate Cp40's complement-inhibiting properties in whole animals. Even after undergoing a single session of dialysis using a pediatric hemodialysis filter with high biocompatibility, healthy animals showed strong complement activation with 5 percent of their C3 being converted to a form that can trigger inflammation and stimulate the immune system.

Ref : http://www.upenn.edu/pennnews/news/penn-researchers-tame-inflammatory-response-kidney-dialysis

Penn researchers find effective way to inhibit inflammatory response during kidney dialysis

SLU researcher discovers new information about how antibiotics stop staph infections

In research published in Proceedings of the National Academy of Sciences, assistant professor of biochemistry and molecular biology at Saint Louis University Mee-Ngan F. Yap, Ph.D., discovered new information about how antibiotics like azithromycin stop staph infections, and why staph sometimes becomes resistant to drugs.

Her evidence suggests a universal, evolutionary mechanism by which the bacteria eludes this kind of drug, offering scientists a way to improve the effectiveness of antibiotics to which bacteria have become resistant.

Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

Yap and her research team studied staph that had been treated with the antibiotic azithromycin and learned two things: One, it turns out that the antibiotic isn't as effective as was previously thought. And two, the process that the bacteria use to evade the antibiotic appears to be an evolutionary mechanism that the bacteria developed in order to delay genetic replication when beneficial.

The team studied the way antibiotics work within the ribosome, the site where bacteria translates the genetic codes into protein. When the bacteria encounter a potential problem in copying its genetic material, as posed by an antibiotic, it has a mechanism to thwart antibiotic inhibition by means of "ribosome stalling" that is mediated by special upstream peptide elements.

Ref  http://www.pnas.org/content/111/43/15379.abstract?sid=94feec3e-058d-4239-97fb-bb9db8f148bb

SLU researcher discovers new information about how antibiotics stop staph infections

Mylan announces U.S. launch of Celecoxib Capsules

In continuation of my update celecoxib

Mylan Inc. (Nasdaq: MYL)      announced the U.S. launch of its Celecoxib Capsules,   50 mg,  100 mg,  200 mg, and 400 mg,  one  of the  first  available  generic  versions        of   Pfizer's elebrex®       Capsules,     which    is   indicated for  the  relief  of the  signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and for the management of acute pain in adults.

Celecoxib Capsules, 50 mg, 100 mg, 200 mg, and 400 mg, had U.S. sales of approximately $2.5 billion for the 12 months ending September 30, 2014, according to IMS Health.

Currently, Mylan has 286 ANDAs pending FDA approval representing $111.6 billion in annual brand sales, according to IMS Health. Forty-five of these pending ANDAs are potential first-to-file opportunities, representing $29.5 billion in annual brand sales, for the 12 months ending June 30, 2014, according to IMS Health.

Mylan announces U.S. launch of Celecoxib Capsules