Novel combination therapy shows strong response in phase 1 trial

In continuation of my update on Sorafenib, Premetrexed,  Vandetanib
"Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial," said Andrew Poklepovic, M.D., lead investigator on the study. "With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study."

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

"Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable," says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

 Sorafenib  Pemetrexed

  Vandetanib    Lapatinib

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best "third drug" that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

"We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer," says Dent. "Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors."

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

"Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy," says Dent. "We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data."

The multiplex assay provided Dent's team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

"The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular 'fingerprint' of the point at which tumors develop resistance to the therapy," says Dent. "Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient's tumor."

Ref : http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=9434

More reasons to eat your broccoli

In continuation of my update on broccoli

University of Illinois researchers have identified candidate genes controlling the accumulation of phenolic compounds in broccoli. Consumption of phenolic compounds, including certain flavonoids, is associated with a lower risk of coronary heart disease, type II diabetes, asthma, and several types of cancer.

"Phenolic compounds have good antioxidant activity, and there is increasing evidence that this antioxidant activity affects biochemical pathways affiliated with inflammation in mammals. We need inflammation because it's a response to disease or damage, but it's also associated with initiation of a number of degenerative diseases. People whose diets consist of a certain level of these compounds will have a lesser risk of contracting these diseases," explains U of I geneticist Jack Juvik.

The researchers crossed two broccoli lines and tested their progeny in terms of total phenolic content and their ability to neutralize oxygen radicals in cellular assays. They then used a genetic technique called quantitative trait locus analysis to search for the genes involved in generating phenolics in the most promising progeny.

By identifying the genes involved in accumulating these compounds, the researchers are one step closer to breeding broccoli and related Brassica vegetables like kale and cabbage with mega-doses of phenolic compounds.

"It's going to take awhile," Juvik notes. "This work is a step in that direction, but is not the final answer. We plan to take the candidate genes we identified here and use them in a breeding program to improve the health benefits of these vegetables. Meanwhile, we'll have to make sure yield, appearance, and taste are maintained as well."

The good news is that phenolic compounds are flavorless and stable, meaning the vegetables can be cooked without losing health-promoting qualities.

Once these vegetables are consumed, the phenolic compounds are absorbed and targeted to certain areas of the body or concentrated in the liver. Flavonoids spread through the bloodstream, reducing inflammation through their antioxidant activity.

"These are things we can't make ourselves, so we have to get them from our diets," Juvik says. "The compounds don't stick around forever, so we need to eat broccoli or some other Brassica vegetable every three or four days to lower the risk of cancers and other degenerative diseases."

Compound shown to reduce brain damage caused by anesthesia in early study

An experimental drug prevented learning deficits in young mice exposed repeatedly to anesthesia, according to a study led by researchers from NYU Langone Medical Center and published June 22 in Science Translational Medicine.

The study results may have implications for children who must have several surgeries, and so are exposed repeatedly to general anesthesia. Past studies have linked such exposure to a higher incidence of learning disabilities, attention deficits and hyperactivity.

 CX546

Specifically, the research team found that the experimental drug CX546, part of the AMPAkine class in clinical trials for several neurological conditions, counters for the dampening effect of anesthesia on nerve signaling. The treatment bolstered nerve cell activity as well as learning ability in mice recovering from repeated exposure to general anesthesia.

"Each year, in the United States alone, more than a million children under age four undergo surgical procedures that require anesthesia, and the numbers are growing," says the study's senior investigator Guang Yang, PhD, assistant professor of anesthesiology at NYU Langone. "There are currently no effective treatments to combat potential toxicity linked to repeated anesthesia, and we would like to change that."

Yang's group took advantage of genetically engineered young mice that have protein markers which glow in response to changes in nerve function. Researchers then used advanced microscopy to visualize activity in their brains, comparing nerve signaling activity in those exposed to anesthesia to those who were not.

The research team found that anesthesia exposure resulted in a prolonged reduction of signal transmission among nerve cells following anesthesia. They also observed that CX546 treatment enhances this transmission, along with learning and memory in mice exposed to anesthesia.

The team studied the anesthetic ketamine, which blocks NMDA (N-methyl-D-aspartate) receptor proteins that enable charged particles like calcium to flow into nerve cells, like electric switches that trigger and shape messages. In contrast, CX546 increases nerve cell activity and calcium influx into nerve cells by enhancing the activity of proteins called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors.

"We were able to counter anesthesia-induced deficits in the formation of connections between nerve cells and related learning problems," says Yang. "This work is an important proof-of-principle study, and opens the door to a new direction for preventing long-term neurocognitive deficits."

Ref : http://stm.sciencemag.org/content/8/344/344ra85 

Compound shown to reduce brain damage caused by anesthesia in early study  

Painkiller That Killed Prince Part of Dangerous Wave of New Synthetic Drugs

In continuation of my update fentanyl

The recent overdose death of rock legend Prince has brought renewed focus on the dangers posed by synthetic opioids -- laboratory-created narcotics tweaked by chemists to produce potentially lethal highs while skirting U.S. drug laws.

 

Prince Rogers Nelson, 57, died April 21 from an overdose of fentanyl, a drug often used to quell pain in cancer patients when traditional opioids prove ineffective.

Despite its legitimate medical uses, fentanyl has acquired a growing reputation as a dangerous street drug thanks to at least a dozen synthetic variants now available to users, according to the U.S. Drug Enforcement Administration (DEA).

And fentanyl is only one of numerous synthetic opioids and designer drugs now flooding the illicit drug market in the United States, DEA acting chief Chuck Rosenberg warned during a U.S. Senate hearing last week.

"We are trying to keep up with a picture that changes almost every day," Rosenberg testified. "We've identified something like 400 new psychoactive substances over the last four or five years."

Another synthetic opioid, U-47700, has been connected to at least 50 deaths nationwide, but is so new to the black market that the DEA has not yet moved to control it, according to the Associated Press.

 U-47700

Synthetic narcotics are dangerous because their potency can far outstrip traditional opioids. For example, fentanyl is 25 to 40 times more potent than heroin, and 50 to 100 times more potent than morphine, said Dr. Mitra Ahadpour. She is a medical officer with the Center for Substance Abuse Treatment in the U.S. Substance Abuse and Mental Health Services Administration.

Rosenberg testified that "fentanyl is so dangerous we've had to instruct our agents that if they touch it or inhale it accidentally, they can die."

Several states reported sharp increases in overdose deaths caused by fentanyl and its analogs in 2014, a health advisory from the U.S. Centers for Disease Control and Prevention noted. Ohio reported 514 fentanyl-related deaths in 2014 compared to 92 in 2013, while Maryland had 185 fentanyl deaths in 2014 compared to 58 the year before.

Ahadpour explained that "if someone is not opioid-tolerant, and uses either pharmaceutical or illicit fentanyl, you have a very high increased chance of respiratory depression and dying. Their breathing slows down, it goes to shallow breathing, and then they stop breathing."

There's wide variation in the potency of these synthetic drugs, and often they are cut with other illicit drugs, Ahadpour added. A user might buy heroin not knowing that it has been cut with fentanyl to increase its potency.

Eleanor Artigiani, deputy director of policy and governmental affairs with the University of Maryland's Center for Substance Abuse Research, said, "They may think they're getting heroin, or they're just buying a Xanax pill off the street, when it's actually one of these other substances."

Artigiani added, "From what I've been hearing recently, sometimes even the people selling these drugs don't know exactly what's in them either. It's like Russian roulette, because you don't really know what you're getting or what effect it's going to have on you."

Toxicology tests concluded that Prince died from a fentanyl overdose, although the medical examiner's report did not say whether the fentanyl was prescription or an illicit analog, CNN reported.

Designer drugs are typically based on medications that have been around for decades, Artigiani said.

Fentanyl was first created in Belgium in the late 1950s, the DEA says, while U-47700 was developed in the 1970s by the pharmaceutical company Upjohn as a potential alternative for morphine.

Black market drug makers come across the formula for a drug, and then tweak the molecule slightly so that it has the same effect on people but isn't technically the same substance, Artigiani explained.

"There's a journal article or a patent document or something that gets produced," she said. "Illicit chemists find it and reproduce it or tweak the molecules to look for other kinds of things that aren't illegal, that haven't been scheduled yet."

Other synthetic opioids on the streets include substances with names like W-18, AH-7921 and MT-45, according to Congressional testimony provided by James Hall, an epidemiologist with the Center for Applied Research on Substance Use and Health Disparities at Nova Southeastern University in Miami.

Illicit drug manufacturers also produce other categories of designer drugs besides synthetic opioids, Hall said, including synthetic versions of cannabinoids, stimulants and hallucinogens.

Nearly all synthetic opioids and other designer drugs are manufactured in China, U.S. National Drug Control Policy Director Michael Botticelli testified before the Senate.

The designer drugs enter the United States either through the mail or across the Mexican or Canadian border, he said, and often are sold at head shops and other retail stores.

State and federal lawmakers are reviewing legislation designed to improve response against new synthetic narcotics, Botticelli said, and the United States is leading discussions with international partners to improve the global response to these drugs.

But right now, law enforcement often is several steps behind the traffickers because U.S. laws aren't flexible enough to quickly outlaw emerging drug analogs, Rosenberg told Congress.

"I almost feel each time I sign an administrative control regulation that I'm simply telling the bad guys, 'Not this one any more. Move over here.' And that's what they do," Rosenberg said. "For every one substance we've controlled, legislatively or administratively, there are 11 more out there that are uncontrolled."

FDA Approves Rayaldee (calcifediol) to Treat Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

OPKO Health, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Rayaldee (calcifediol) extended release capsules for the treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Rayaldee is a patented extended release product containing 30 mcg of a prohormone called calcifediol (25-hydroxyvitamin D3).

 calcifediol

"FDA's approval of Rayaldee represents an important milestone for OPKO," noted Dr. Phillip Frost, CEO and Chairman of OPKO. "Rayaldee is the first product to receive FDA approval for this important indication and is one of OPKO's many pharmaceutical products being developed for significant medical problems which will benefit from new treatment options."

Results from two 26 week placebo controlled, double blind phase 3 trials demonstrated that a larger proportion of stage 3 or 4 CKD patients with SHPT and vitamin D insufficiency achieved ≥30% reductions in plasma intact parathyroid hormone (iPTH) when treated with Rayaldee than with placebo. Vitamin D insufficiency was corrected in more than 80% of the patients receiving Rayaldee compared with less than 7% of subjects receiving placebo. Mean serum calcium and phosphorus levels increased by 0.1 mg/dL during Rayaldee treatment compared to placebo treatment, but these changes were deemed clinically irrelevant. No differences in Rayaldee's efficacy or safety were observed between patients with stage 3 CKD or stage 4 CKD.

"Rayaldee fills a large void in the current treatment options for SHPT in predialysis patients," commented Dr. Charles W. Bishop, CEO of OPKO's Renal Division. "The current standard of care is high dose vitamin D supplementation, an approach for treating SHPT that is neither FDA approved nor demonstrated to be safe and effective in this population. SHPT is a progressive disease that becomes increasingly debilitating and difficult to treat, necessitating timely and effective treatment."

"Rayaldee is an important new option for treating SHPT in patients with stage 3 or 4 CKD and vitamin D insufficiency," stated Kevin J. Martin, Director of Research, Division of Nephrology at Saint Louis University School of Medicine. "The great majority of SHPT cases in this patient population are associated with vitamin D insufficiency, a problem that Rayaldee can correct."

About Rayaldee

Rayaldee (calcifediol) extended release capsules are approved by the U.S. Food and Drug Administration (FDA) for the treatment of SHPT in adult patients with stage 3 or 4 CKD and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Rayaldee has a patented formulation designed to raise serum total 25-hydroxyvitamin D (prohormone) concentrations to targeted levels (at least 30 ng/mL) and to reduce elevated iPTH. OPKO expects to launch Rayaldee in the U.S. through its dedicated renal sales force in the second half of 2016. Rayaldee is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis. The full prescribing information for Rayaldee will be available at www.opkorenal.com.

Potential side effects of Rayaldee include hypercalcemia (elevated serum calcium), which can also lead to digitalis toxicity, and adynamic bone disease with subsequent increased risk of fractures if intact PTH levels are suppressed by Rayaldee to abnormally low levels. Severe hypercalcemia may require emergency attention; symptoms of hypercalcemia may include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss. Digitalis toxicity can be potentiated by hypercalcemia of any cause. Excessive administration of Rayaldee can cause hypercalciuria, hypercalcemia, hyperphosphatemia, or oversuppression of intact PTH. Common symptoms of vitamin D overdosage may include constipation, decreased appetite, dehydration, fatigue, irritability, muscle weakness, or vomiting. Patients concomitantly taking cytochrome P450 inhibitors, thiazides, cholestyramine, phenobarbital or other anticonvulsants may require dose adjustments and more frequent monitoring.

The most common adverse reactions in clinical trials (≥3% and more frequent than placebo) were anemia, nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure and constipation.

Blueberries' health benefits better than many perceive

In continuation of my update on blueberries

Qu and her colleagues wanted to determine how much consumers know about blueberry health benefits and see if there's a knowledge gap with blueberry health benefits among demographic groups. Using their findings, they will identify promotional opportunities for Florida blueberries.

Researchers surveyed more than 2,000 people in 31 states -- mostly on the East Coast and in the Midwest -- to see what they know about the health benefits of blueberries. Most were aware of the benefits of blueberries in warding off cancer and lowering the risk of heart disease. The UF/IFAS study also found that low-income populations tend to know less about blueberry health benefits.

"People being more familiar with blueberries as deterrents for cancer and heart disease may be related to the high general awareness of these two diseases," Qu said. "The fact that cancer and heart diseases are the leading causes of death in America may have led to more personal research related to preventing the diseases, leading to the respondents being exposed to these findings more than other benefits."

To help promote blueberries' health benefits, Qu and her colleagues suggest holding events during blueberry season, such as tastings or u-picks to draw consumers to the crop while providing a vehicle for information about blueberry health benefits.

Blueberries' health benefits better than many perceive  

Darapladib drug can protect against vision loss in diabetic patients

Researchers at Queen's University Belfast and University College London have discovered that a drug, originally developed to treat cardiovascular disease, has the potential to reduce diabetes related blindness.

According to recent WHO global estimates, 422 million people have diabetes. One of the most common complications of this disease is vision loss.  Diabetic Macular Oedema occurs in approximately 7 per cent of patients with diabetes and is one of the most common causes of blindness in the Western World. In the UK, this sight-threatening complication of diabetic retinopathy is associated with estimated health and social care costs of £116 million. The socio-economic burden will only increase with prevalence of diabetes rising by more than 50 per cent by 2030.

Queen's and UCL researchers, in partnership with  GlaxoSmithKline, found that the drug Darapladib inhibits an enzyme which is increased in people with diabetes and causes blood vessel leakage in the eye which leads to swelling of the retina and severe vision loss.

Currently, the most common treatments for patients with Diabetic Macular Oedema is an injection of a drug directly into to the eye every 4-6 weeks.  This therapy is very expensive and not effective for about half of all patients with Diabetic Macular Oedema.

The discovery by the Queen's and UCL teams demonstrates that Darapladib in form of a tablet has potential to reduce the need for monthly injections and provide protection against vision loss in a much wider group of patients with diabetes.

Speaking about the breakthrough, Professor Alan Stitt, from the Centre for Experimental Medicine at Queen's University, said: "Diabetes-related blindness is caused by high blood sugar levels damaging the blood vessels in the retina.  We have found that an enzyme called Lp-PLA2 which metabolises fats in the blood contributes to blood vessel damage and leakiness in the retina. The drug Darapladib acts as inhibitor of Lp-PLA2, and was originally developed for cardiovascular disease. Based on our break-though we are now planning a clinical trial and if successful we could soon see an alternative, pain-free and cost effective treatment for diabetic related blindness."

Dr Patric Turowski from the UCL Institute of Ophthalmology said: "With our study we show that a blood lipid produced by Lp-PLA2 constitutes a novel trigger factor in diabetic macular oedema and that use of Darapladib may not only constitute an cost-effective alternative to current DMO treatments but has the potential to be effective for patients that currently do not respond to standard treatment."

Fixed-dose combination of sacubitril and valsartan for heart failure shows differing added benefit

In continuation of my update on Valsartan and Sacubitril

           Valsartan  Sacubitril 

The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function. In its early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) derived an indication of considerable added benefit versus the appropriate comparator therapy enalapril from the data: The positive effects regarding mortality, hospitalizations and quality of life largely outweighed the negative effect in non-severe side effects.

In the following commenting procedure, the drug manufacturer subsequently submitted sensitivity analyses and data, and a possible effect modification by the subgroup characteristic diabetes mellitus was pointed out. IQWiG investigated this in an addendum and concluded that there is an indication of a minor added benefit for diabetes patients. For patients without diabetes, in contrast, an indication of considerable added benefit of the drug combination remains.

Sensitivity analyses did not change assessment of the added benefit

The PARADIGM-HF study, on which the dossier was based, contained a so-called run-in phase to ensure that the participants tolerated the target dose of the study medication. About 20 per cent of the participants dropped out of the study in this phase. As noted by IQWiG in its dossier assessment, the rate of adverse events may be underestimated as a result, and more so under the drug combination than in the comparator arm.

To account for this, the manufacturer now presented sensitivity analyses. However, these analyses neither considered the outcomes of interest nor were methodologically adequate to remedy this deficiency. They did therefore not change the assessments from the dossier assessment.

Quality of life: indication of added benefit confirmed

Regarding health-related quality of life and health status, the manufacturer subsequently submitted analyses that increase the certainty of conclusions in comparison with the dossier assessment. For quality of life, there is now an indication of an added benefit both for clinically relevant improvement and for clinically relevant worsening. For health status, there is still no advantage of sacubitril/valsartan. Hence there is still no hint of an added benefit for this outcome.

Diagnosis of diabetes as relevant subgroup characteristic

There was proof of an effect modification in the outcome "mortality": Whereas there was an indication of an added benefit of sacubitril/valsartan in comparison with enalapril for patients without diabetes mellitus, there was no hint of an added benefit for patients with diabetes.

Overall, there were therefore still both positive effects and a negative effect. Due to the effect modification by the characteristic "diabetes", an indication of minor added benefit remains for patients with this disease, whereas there is still an indication of considerable added benefit for patients without diabetes.

Highly efficient bacterial agent could improve treatment of Wilson disease

 

In the 'Journal of Clinical Investigation', scientists at the Helmholtz Zentrum München describe a small peptide that very efficiently binds excess copper from liver cells. This molecule comes from a bacterium's bag of tricks and could be suitable for treating Wilson disease. In an experimental model it has already proven superior to conventional medicines.

In Wilson disease, also called Wilson's disease or hepatolenticular degeneration, the body is no longer able to excrete excess copper ingested from food into the intestines via the bile. Instead, the copper is stored in the liver and other organs, where it can cause severe damage. Doctors accordingly employ medicines called chelators that bind the surplus copper. These life-long treatments are especially effective if commenced during the early stages of the disease. The drugs must be taken several times a day, are repeatedly associated with undesired effects, and, particularly in the event of a late diagnosis of the disease, are often ineffective, so that a liver transplant can be necessary as the last resort.

Researchers headed by PD Dr. Hans Zischka, head of the Oxidative Cell Death research group at the Institute of Molecular Toxicology and Pharmacology at the Helmholtz Zentrum München have now conducted a detailed examination of a bacterial agent that could improve the disease treatment. They looked to the bacterium Methylosinus trichosporium, which requires large quantities of copper due to its special methane metabolism. In order to acquire the necessary metal, it excretes the methanobactin molecule, which very efficiently binds copper.

In order to check if methanobactin is also suitable for binding copper from the body, the researchers used an in vivo model for the disease that had the same genetic defect as that found in humans. "We were able to observe that even acute stages of Wilson disease reversed with methanobactin," reports Josef Lichtmannegger, who, together with Christin Leitzinger, is the study's first author. Further analyses showed that the improvement was due to a sharp decline in the copper quantities. Especially the mitochondria, known as the "powerhouse of the cell", greatly profited from the dropping copper levels and were able to resume their full function. Methanobactin hindered the death of liver cells and prevented liver failure.

The researchers then compared methanobactin to chelators that are currently used in hospitals. Unlike the chelators, methanobactin was able to eliminate the copper overload in the liver cells within a few days, even in stages of severe damage, and prevent organ failure. The agent was also very well tolerated in the model.

"We hope that our work will make it possible to improve the treatment of Wilson disease and reduce the number of liver transplants," states Zischka, the study leader. It is conceivable that in the long run it will be possible to replace the current use of less effective chelators several times a day with short treatment cycles using methanobactin. Clinical studies are now necessary to test this.

Researchers find promising drugs that could lead to first antidote for radiation exposure

University of Virginia School of Medicine researchers have identified promising drugs that could lead to the first antidote for radiation exposure that might result from a dirty bomb terror attack or a nuclear accident such as Chernobyl.

Some of the compounds, including the drug rapamycin, have previously been shown toextend life in organisms such as worms and flies, though it's unknown if they would have the same benefit in humans. UVA's research suggests that these compounds, or similar drugs, might counter the deadly effects of ionizing radiation.

 rapamycin

Currently there is no treatment for people exposed to lethal doses of radiation; doctors can only try to ease their suffering until death. "If you're exposed to a very, very high dose, it's rapid deterioration and immediate death," explained John S. Lazo, PhD, of UVA's Department of Pharmacology. "It's the lower doses that people - particularly governments - are concerned about. The type of exposure that might result from a dirty bomb or a nuclear accident. How do we alleviate the effects? What's the antidote? Right now, we just don't have anything."

Innovative Approach

Lazo and his colleague Elizabeth R. Sharlow, PhD, screened a library of more than 3,400 existing drugs, vitamins and other compounds to identify ones that might help cells withstand the effects of radiation exposure. The goal was to keep stem cells - the cells that produce the various cell types in the body - alive long enough to repair the damage caused by radiation.

"We wanted to find already approved drugs that would potentially keep stem cells, or progenitor cells, alive after radiation exposure," Sharlow said. "That's very much of interest to the NIH [National Institutes of Health] right now: How can we keep those se

lf-renewing populations alive so they can actually help heal the effects of radiation exposure?"

After they identified potential leads, Sharlow created 3D computer models to compare the substances' chemical structures. That analysis identified a cluster of promising compounds with similar structures - a tantalizing lead in the quest for an antidote. "If you're a drug hunter, the way we are, this is really cool information," Lazo said. "Because you can say, 'Now I will look in the universe of 40 million compounds. What else looks like that? Are they useful?'"

He noted that it is unlikely any one drug or compound will work on its own. "A lot of us in this field think it will be a cocktail of things you take," he said. "And if you think you need cocktails, you need the individual ingredients. That's why we think this is pretty important - because it's providing new ingredients for that cocktail."

Natural molecule NAC could benefit patients with Parkinson's disease

The natural molecule, n-acetylcysteine (NAC), with strong antioxidant effects, shows potential benefit as part of the management for patients with Parkinson's disease, according to a study published today in the journal PLOS ONE. Combining clinical evaluations of a patient's mental and physical abilities with brain imaging studies that tracked the levels of dopamine, the lack of which is thought to cause Parkinson's, doctors from the Departments of Integrative Medicine, Neurology, and Radiology, at Thomas Jefferson University showed that patients receiving NAC improved on both measures.

 Acetylcysteine

Current treatments for Parkinson's disease are generally limited to temporarily replacing dopamine in the brain as well as some medications designed to slow the progression of the disease process. Recently, researchers have shown that oxidative stress in the brain may play a critical role in the Parkinson's disease process, and that this stress also lowers levels of glutathione, a chemical produced by the brain to counteract oxidative stress. Studies in brain cells showed that NAC helps reduce oxidative damage to neurons by helping restore the levels of the antioxidant glutathione. NAC is an oral supplement that can be obtained at most nutrition stores, and interestingly also comes in an intravenous form which is used to protect the liver in acetaminophen overdose.

"This study reveals a potentially new avenue for managing Parkinson's patients and shows that n-acetylcysteine may have a unique physiological effect that alters the disease process and enables dopamine neurons to recover some function," said senior author on the paper Daniel Monti, M.D., M.B.A., Director of the Myrna Brind Center of Integrative Medicine, and the Brind-Marcus Center of Integrative Medicine at Thomas Jefferson University.

In this study, Parkinson's patients who continued their current standard of care treatment, were placed into two groups. The first group received a combination of oral and intravenous (IV) NAC for three months. These patients received 50mg/kg NAC intravenously once per week and 600mg NAC orally 2x per day on the non IV days. The second group, the control patients, received only their standard of care for Parkinson's treatment. Patients were evaluated initially, before starting the NAC and then after three months of receiving the NAC while the control patients were simply evaluated initially and three months later. The evaluation consisted of standard clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS), a survey administered by doctors to help determine the stage of disease, and a brain scan via DaTscan SPECT imaging, which measures the amount of dopamine transporter in the basal ganglia, the area most affected by the Parkinson's disease process. Compared to controls, the patients receiving NAC had improvements of 4-9 percent in dopamine transporter binding and also had improvements in their UPDRS score of about 13 percent.

"We have not previously seen an intervention for Parkinson's disease have this kind of effect on the brain," said first author and neuro-imaging expert Andrew Newberg, M.D., Professor at the Sidney Kimmel Medical College at Jefferson and Director of Research at the Myrna Brind Center of Integrative Medicine. The investigators hope that this research will open up new avenues of treatment for Parkinson's disease patients.

Rice University researchers synthesize new anti-cancer agent

Rice University scientists have synthesized a novel anti-cancer agent, Thailanstatin A, which was originally isolated from a bacterial species collected in Thailand.

 

Thailanstatin A

Thailanstatin A fights cancer by inhibiting the spliceosome, the machinery in the cell that edits messenger RNA after transcription from DNA but before its translation into proteins.

Rice synthetic chemist K.C. Nicolaou and his group reported their success in the Journal of the American Chemical Society.

Nicolaou and his colleagues specialize in the synthesis of potential therapeutic agents that are found in nature but in amounts too small for thorough biological evaluation or clinical use. He is best known for the total synthesis of paclitaxel, a drug commonly used to treat a number of cancers.

The researchers explained that the spliceosome, a complex of proteins and ribonucleoproteins that regulate DNA splicing, is more active and displays higher mutation rates in cancer cells than in healthy cells, which makes it a valid target for investigation.

"This cellular machinery edits mRNA as it emerges from the transcription of DNA through site-specific removal of introns (noncoding regions of DNA) and splicing the remaining exon (coding) sequences prior to translation," Nicolaou said. "Thailanstatin A interferes with this mechanism."

He said the synthesis of Thailanstatin A, first isolated from burkholderia thailandensis bacteria, opens the way to construct and test variations of the molecule. "These studies will be directed toward optimization of the pharmacological properties of this new natural product as part of a drug discovery and development program targeting new therapies for cancer," Nicolaou said.

The program can take two directions, he said: one directed toward high-potency compounds that could be used as payloads for antibody drug conjugates and the other toward selective agents that can kill cancer cells with minimal damage to healthy cells.

The first paradigm is currently a frontier approach for the development of targeted and personalized cancer therapies, while the second represents a more traditional approach that could also lead to powerful anti-cancer drugs, Nicolaou said. "Thailanstatin A exhibits just the right potency to be diverted to either approach through a reiterative molecular design, chemical synthesis and biological evaluation process," he said.

"We're excited about this new molecule and its analogs because of their unique biological properties and the prospects of working collaboratively with industrial and academic partners to advance them toward the clinic," Nicolaou said.

Rice University researchers synthesize new anti-cancer agent