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