New chemo drug gentler on fertility, tougher on cancer

We know that, Arsenic trioxide is the inorganic compound with the formula As₂O₃. This commercially important oxide of arsenic is the main precursor to other arsenic compounds, including organoarsenic compounds. Approximately 50,000 tonnes are produced annually.Many applications are controversial given the high toxicity of arsenic compounds.

A Tiny Trojan Horse

The chemotherapy drug, arsenic trioxide, is packed into a very tiny Trojan horse called a nanobin. The nanobin consists of nano-size crystalline arsenic particles densely packed and encapsulated in a fat bubble. The fat bubble, a liposome, disguises the deadly cargo   half a million drug molecules.

"You have to wallop the tumor with a significant dose of arsenic but at the same time prevent exposure to normal tissue from the drug," said O'Halloran. The fat bubble is hundreds of times smaller than the average human cell. It is the perfect size to stealthily slip through holes in the leaky blood vessels that rapidly grow to feed tumors. The local environment of the tumor is often slightly acid; it is this acid that causes the nanobin to release its drug cargo and deliver a highly effective dose of arsenic where it is needed.

The scientists show this approach to packaging and delivering the active drug has the desired effect on the tumor cells but prevents damage to ovarian tissue, follicles or eggs.

While the drug is gentle on fertility, it is ferocious on cancer. When tested against lymphoma, it was more potent than the drug in its traditional free form.

"The drug was designed to maximize its effectiveness but reduce fertotoxicity," said O'Halloran, also the Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. "Many cancer drugs cause sterilization, that's why the reproductive tract is really important to focus on in the new stages of drug design. Other body systems get better when people stop taking the drug, but fertility you can't recover."

Arsenic trioxide was approved a few years ago for treating some types of blood cancers such as leukemia in humans, but O'Halloran thinks the arsenic trioxide nanobins can be used against breast cancer and other solid tumors. In his previously published preclinical research, nanobins were effective in reducing tumor growth in triple-negative breast cancer, which often doesn't respond well to traditional chemotherapy and has a poor survival rate.

Quick Test For Fertility Toxicity

Woodruff was able to show early effects of the drug on fertility by using an in vitro follicle culture and a quick, simple new test she developed. She compared the fertotoxicity of the nanobin and free drug and found the nanobin was much less toxic to female fertility than the free drug in the experimental model.

"The system can be adapted very easily for any cancer drug under development to get an early peek under the tent,"said Woodruff, also the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg. "As this new drug goes forward in development, we can say this is a good drug for young female cancer patients who are concerned about fertility."

The information gained from the toxicity test will help inform the treatment decisions of oncologists and their young female cancer patients to improve their chances of creating a future family.

"They may prescribe less toxic drug regimens or refer them to specialists in fertility preservation," Woodruff said...

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0058491

New chemo drug gentler on fertility, tougher on cancer

Positive results from Affinium Pharmaceuticals' Phase 2a clinical trial of AFN-1252 in ABSSSI

We know that, AFN-1252, is a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis. 

Now, Affinium Pharmaceuticals announced today that its Phase 2a clinical trial evaluating oral AFN-1252   in acute bacterial skin & skin structure infections (ABSSSI) demonstrated excellent efficacy and safety data, marking a significant proof-of-concept milestone for Affinium's first-in-class, novel antibiotic targeted against bacterial fatty acid biosynthesis inhibition (FabI inhibitors).

A clinical study in 103 patients from 18 centers in the USA and Canada confirms excellent efficacy, safety and tolerability of 200 mg of oral AFN-1252 dosed twice daily for 5-14 days in patients with acute bacterial skin and skin structure infections (ABSSSI) due to Staphylococcus". Patients were recruited from outpatient or emergency room settings.   The enrolled patients had a variety of skin infections of ≥ 75 cm² in size, including severe abscesses (38%), cellulitis (27%), and wound infections (35%).  Investigators had the option of adding a second antibiotic to cover other potential pathogens or admitting the patient into the hospital. The vast majority of the patients were treated with oral AFN-1252 as monotherapy in the outpatient setting based on the suspicion of staphylococci from the clinical presentation and pretreatment Gram stain.  This study fully utilized recent FDA guidances for clinical trials in ABSSSI, including both entry and efficacy criteria.

Positive results from Affinium Pharmaceuticals' Phase 2a clinical trial of AFN-1252 in ABSSSI

Clinical Trials Move to the Petri Dish

In continuation of my update on azithromycinZithromax ....

The common antibiotic Zithromax received a new warning label from the U.S. Food and Drug Administration indicating it could cause dangerous arrhythmias in people with pre-existing heart conditions. Now, researchers at the Stanford University School of Medicine describe a “clinical trial in a dish” using patient-specific induced pluripotent stem, or iPS, cells to predict whether a drug will dangerously affect the heart’s function. The technique may be more accurate than the current in vitro drug-safety screening assays used by pharmaceutical companies, say the researchers, and may better protect patients from deadly side effects of common medications.

The technique allows scientists for the first time to test drugs directly on cells with mutations that cause hereditary cardiac diseases, rather than on the genetically modified human embryonic kidney cells or the Chinese hamster ovarian cells currently being used to detect cardiac toxicity.

The use of patient-specific iPS cells may help drug designers winnow heart-safe medications from those like the blockbuster anti-inflammatory drug Vioxx, which was withdrawn from the market because of unanticipated adverse cardiovascular events. It may also allow clinicians to identify sub-groups of patients, such as those with certain types of cardiac conditions, who should not be given certain drugs.

“Right now, the first time any drug sees a human heart cell is in a phase-1 clinical trial,” said Andrew Lee, a Stanford medical student and one of three lead authors of the study. “If adverse effects are seen, it can result in patient deaths, as in the case of the anti-inflammatory drug Vioxx or with cisapride, a drug previously used to treat digestive problems in people with diabetes. Right now, there are really no systematic studies to identify those people who are at risk.” Lee works in the laboratory of Joseph Wu, MD, PhD, who co-directs the Stanford Cardiovascular Institute, where the research was conducted.

The researchers anticipate that the technique, if adopted, could save millions of dollars and thousands of lives by streamlining the drug-testing process and increasing its sensitivity.

Clinical Trials Move to the Petri Dish

Soybeans can prevent cancer

Soybean meal is a bi-product following oil extraction from soybean seeds. It is rich in protein, which usually makes up around 40% of the nutritional components of the seeds and dependent on the line, and can also contain high oleic acid (a monounsaturated omega-9 fatty acid).

The study looked at the role soybeans could have in the prevention of cancer. Using a variety of soybean lines which were high in oleic acid and protein, the researchers looked to monitor bioactivity between the peptides derived from the meals of soybean and various types of human cancer cells.

The study showed that peptides derived from soybean meal significantly inhibited cell growth by 73% for colon cancer, 70% for liver cancer and 68% for lung cancer cells using human cell lines. This shows that the selected high oleic acid soybean lines could have a potential nutraceutical affect in helping to reduce the growth of several types of cancer cells.

Soybeans can prevent cancer

New class of anti-malarial compounds discovered

A group of researchers from 16 institutions around the world has identified a new class of anti-malarial compounds that target multiple stages of the malaria parasite's life cycle  These compounds could potentially be developed into drugs that treat and prevent malaria infection. Known as 4-(1H)-quinolone-3-diarylethers, the candidate anti-malarials are derived from a compound called endochin that effectively treats malaria in birds. When tested in the laboratory and in mice, the compounds demonstrated strong activity againstPlasmodium falciparum and Plasmodium vivax, the two parasites that cause most human cases of malaria. Transmitted via a mosquito bite, malaria causes cycles of chills, fever and fatigue, and is responsible for roughly 660,000 deaths per year, according to the World Health Organization. New drugs are needed because of the emergence of malaria-inducing parasites that are resistant to existing medications.

Of the 4-(1H)-quinolones, the researchers focused their efforts on the compound ELQ-300, which inhibited malaria parasites during the erythrocytic stage, when they cause symptoms in humans; as well as during the gametocyte and developmental stages in the mosquito, when the parasites are transmitted. In addition, when ELQ-300 was administered to mice infected with the Plasmodium species that cause malaria in mice, the infection was cured. The study results also suggested that the compound could be adapted into a once-daily dose in humans and would be slow to engender resistance. The researchers are currently proceeding with preclinical development of ELQ-300 (see the structure below).

Ref :1.  http://www.niaid.nih.gov/news/newsreleases/2013/Pages/ELQ300.aspx
2. http://stm.sciencemag.org/content/5/177/177ra37.short?rss=1

New class of anti-malarial compounds discovered

Drug treatment corrects autism symptoms in mouse model

The researchers tested suramin,  a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916 -- in mice. They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms. The drug restored 17 types of multi-symptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination and normalizing mitochondrial metabolism.

"The striking effectiveness shown in this study using APT to 'reprogram' the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders," Naviaux said.

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057380

 Drug treatment corrects autism symptoms in mouse model

Disinfectant mouthwashes may be effective against cancers of the mouth and throat

Patients who suffer from gingivitis are often advised to use disinfectant mouthwashes. In the future, the active ingredients in these products could be used in a completely different area. Chlorhexidin and Alexidin increase programmed cell death and may be effective against cancers of the mouth and throat.

Berg and his co-workers were successful: Chlorhexidin (below left structure), the active component in commercial oral disinfectants such as Chlorhexamed, Chlorhexal, Periogard, Corsodyl, and Chlorohex; as well as Alexidin (below right structure), the active component in Esemdent, both inhibit the binding of the apoptosis inhibitor to the apoptosis trigger. Chlorhexidin's effect is specific, while Alexidin has additional very weak effects on other proteins.

Why are apoptosis proteins interesting? Apoptosis is decreased in tumor cells, so the cells do not die off and continue to divide. One reason for this is that they produce too much of the apoptosis-inhibiting protein. In experiments with cultures of cells from various tongue and throat carcinomas, both compounds caused increased apoptosis. This effect is much stronger in the cancer cells than in healthy cells. It may be possible to use these drugs in therapeutic applications.

The researchers hope to find other protein-protein interactions that could be targeted with approved small-molecule drugs....

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1521-3773/homepage/press/201311press.html

Disinfectant mouthwashes may be effective against cancers of the mouth and throat

Researchers identifiy elusive anti-cancer property of vitamin E

Researchers identifiy elusive anti-cancer property of vitamin E

Japanese P2 study shows potential of combined vaccine and steroid drug in castration resistant PCa

 In continuation of my update on dexamethasone

Multi-peptide vaccination therapy combined with the low-dose steroid drug dexamethasone shows promise in treating chemotherapy-naive castration resistant prostate cancer (CRPC) patients.

Japanese P2 study shows potential of combined vaccine and steroid drug in castration resistant PCa

New drugs may improve quality of life for people with Parkinson's disease

In the study, 225 people were randomized to receive either eight weeks of stable dose treatment with a placebo or the drug droxidopa, (see structure)  

 

which converts to norepinephrine. After one week of stable treatment, those who received the drug had a clinically meaningful, two-fold decrease in the symptoms of dizziness and lightheadedness, when compared to placebo. They also had fewer falls, or 0.38 falls per patient per week, compared to 1.73 for those receiving a placebo on average over the entire 10-week study duration.

The second study looked at treatment with a new drug for "wearing-off" that occurs with people who have been taking levodopa for several years. As each dose wears off, people experience longer periods of time where the motor symptoms do not respond to levodopa. For the study, 420 people who were experiencing an average of six hours of "off" time per day received a placebo or one of four dosages of the drug tozadenant in addition to their levodopa for 12 weeks. People receiving two of the dosages of the drug had slightly more than an hour less off time per day at the end of 12 weeks than they had at the start of the study. They also did not have more troublesome involuntary movements during their "on" time, called dyskinesia, that can occur. 

 
The third study looked at 321 people with early Parkinson's disease whose symptoms were not well-controlled by a dopamine agonist drug. For the 18-week study, the participants took either the drug rasagiline or a placebo in addition to their dopamine agonist. At the end of the study, those taking rasagiline had improved by 2.4 points on a Parkinson's disease rating scale. In addition, rasagiline was well tolerated with adverse events similar to placebo.

New drugs may improve quality of life for people with Parkinson's disease

Breakthrough in battle against leukemia

The research team has demonstrated that leukaemic cells can be eradicated by removing a carbohydrate modification displayed on the cell's surface.

Director of Griffith University's Institute for Glycomics, Professor Mark von Itzstein is the Australian team leader. He said the discovery is an important advance against leukemia, a cancer of malignant white blood cells that multiply uncontrollably. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer.

"We have found that the leukaemic cell has an altered cell surface carbohydrate decoration compared to normal cells and this also conveys resistance to drug treatment," Professor von Itzstein said.

"We have now shown that with the removal of this carbohydrate alteration the cells die."

Professors Nora Heisterkamp and John Groffen, leaders of the US-based team, Professor von Itzstein and their colleagues have published their research findings in the latest edition of the Journal of Experimental Medicine.

Professor von Itzstein said the research could lead to new ways to fight the disease, particularly where it has become treatment resistant.

"Up until 40 years ago, only one child in five survived ALL," but advances in chemotherapy have changed that outcome and now nearly 80 percent of children with ALL will be cured," Professor von Itzstein said.

"For the remaining 20 percent, however, the disease returns necessitating additional rounds of intensive chemotherapy. Unfortunately, most relapsed patients die within one year because their cancer cells are resistant to chemotherapy.

Breakthrough in battle against leukemia

Drug may improve outcomes after heart attack

 We know that, Eplerenone (INN)  is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, or estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarction. It is marketed by Pfizer under the trade name Inspra. Eplerenone is a potassium-sparing diuretic, meaning that it helps the body get rid of water but still keep potassium....

Now,

The REMINDER (Reduction of heart failure morbidity in patients with acute ST-elevation myocardial infarction) trial was a randomized, double-blind trial of 1,012 patients who had a heart attack caused by a complete blockage of one of the heart's arteries. Patients had no signs or history of heart failure. They were given either eplerenone or placebo in addition to standard therapy. Overall, patients taking eplerenone were 38 percent less likely to have poor outcomes than those given a placebo.

Eplerenone counteracts a hormone called aldosterone, which can increase blood pressure. The drug is currently approved to treat hypertension and as a treatment for patients who have heart failure several days after a heart attack.

"This is the first randomized trial to test a mineralocorticoid receptor agonist during the acute phase of heart attack, and the results suggest a clinical benefit," said Gilles Montalescot, MD, PhD, lead investigator of the study and professor of cardiology and head of the Cardiac Care Unit at Pitié-Salpétrière Hospital, Paris.

About 5.8 million Americans have heart failure, a condition in which the heart cannot pump enough blood to meet the body's oxygen and energy needs. Improvements in heart attack treatment have increased chances of survival, but damage after heart attack is one risk factor for heart failure. Clinical trials and registries show that in the 30 days after a first heart attack, between 8.6 percent and 40 percent of patients will be diagnosed with heart failure.

Drug may improve outcomes after heart attack

Clot-busting drug as effective as angioplasty, study suggests

 A clot-busting therapy may benefit some heart attack patients who cannot have immediate angioplasty, according to research presented today at the American College of Cardiology's 62nd Annual Scientific Session.

Clot-busting drug as effective as angioplasty, study suggests

Promising new drug treats and protects against radiotherapy-associated oral mucositis

Mouse model studies show that administered genetically or topically, protein Smad7 protects against or heals mouth sores commonly associated with cancer treatment.

Ref : http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3118.html

Promising new drug treats and protects against radiotherapy-associated oral mucositis

Bitter melon juice prevents pancreatic cancer in mouse models

"Three years ago researchers showed the effect of bitter melon extract on breast cancer cells only in a Petri dish. This study goes much, much farther. We used the juice  people especially in Asian countries are already consuming it in quantity. We show that it affects the glucose metabolism pathway to restrict energy and kill pancreatic cancer cells," says Rajesh Agarwal, PhD, co-program leader of Cancer Prevention and Control at the CU Cancer Center and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences.

Agarwal's interest came from connecting the dots of existing research in a novel way. Diabetes tends to presage pancreatic cancer and bitter melon has been shown to effect type-II diabetes, and has been used for centuries against diabetes in the folk medicines of China and India. Following this line of thinking, Agarwal and colleagues wondered what would happen if they closed out the middle man of diabetes and directly explored the link between bitter melon and pancreatic cancer.

The result, Agarwal says, is, "Alteration in metabolic events in pancreatic cancer cells and an activation of the AMP-activated protein kinase, an enzyme that indicates low energy levels in the cells."

Perhaps not coincidentally, bitter melon also regulates insulin secretion by pancreatic beta cells. After studies in cell cultures, the group showed that mouse models of pancreatic cancer that were fed bitter melon juice were 60 percent less likely to develop the disease than controls.

"It's a very exciting finding," Agarwal says. "Many researchers are engineering new drugs to target cancer cells' ability to supply themselves with energy, and here we have a naturally-occurring compound that may do just that."

The Agarwal Lab is now applying for grants that will allow them to move the study of bitter melon into further chemoprevention trials in mouse models of pancreatic cancer.

Ref : dx.doi.org/10.1093/carcin/bgt081

 

Bitter melon juice prevents pancreatic cancer in mouse models