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