Tumor-Targeting Drug Shows Potential for Treating Bone Cancer Patients

Preclinical study shows BMTP-11 targets high-risk osteosarcoma

The treatment of osteosarcoma, the most common tumor of bone, is challenging. A study led by The University of Texas MD Anderson Cancer Center found a drug known as bone metastasis-targeting peptidomimetic (BMTP-11) has potential as a new therapeutic strategy for this devastating illness.

Results from the preclinical study, which looked at BMTP-11 alone and in combination with the chemotherapy agent gemcitabine, were published in the July 11, 2017, online issue of Proceedings of the National Academy of Sciences.

Although osteosarcoma is a relatively rare cancer, it is a leading disease-related cause of death in children and young adults ages 10 to 20. However, over the last 25 years, the five-year survival rate has remained unchanged, and the treatment options for these patients are few. In addition, the side effects of available treatment options often are significant and cumulative, and may cause other health problems and damage to major organs.

“What’s novel about this treatment is that BMTP -11 targets the tumor and spares other organs,” said Valerae O. Lewis, M.D., chair of Orthopaedic Oncology at MD Anderson. “We believe this study lays the groundwork for a clinical trial for the treatment of osteosarcoma without the cumulative and mortal side effects seen with the current treatment options.”

The study results identified IL-11Rα as an osteosarcoma cell surface receptor that correlated with tumor progression and poor prognosis in osteosarcoma patients. The team, which included co-authors Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., both of whom worked on the study while at MD Anderson and are now professors at the University of New Mexico Health Sciences Center (UNMSC) School of Medicine, also illustrated that IL-11Rα and IL-11 are up-regulated in human metastatic osteosarcoma cell lines, and this correlated with the development of lung metastases in mouse models of the disease. The metastatic potential of the osteosarcoma cell lines could be modulated by targeting IL-11Rα expression. Death from respiratory failure linked to metastasis to the lungs remains a significant problem among osteosarcoma patients.

“We were able to document anti-tumor activity against osteosarcoma models,” said Pasqualini. “Given that a first-in-human trial of BMTP-11 has recently been reported, one would hope that this proof-of-concept study might lead to early translational clinical trials in human osteosarcoma as a logical next step in the context of an unmet medical oncology need.”

Arap added that “this work provides a preclinical foundation for the potential design and development of a second line combination therapy regimen composed of conventional chemotherapeutics plus the targeted candidate drug BMTP-11 for application in unfortunate patients with recalcitrant osteosarcoma.”

Eli Lilly, Biogen, and Neurotrope Fight to Find Viable Treatment for Alzheimer’s Disease

Repeated attempts to treat or even slow the relentless progression of Alzheimer’s disease by targeting just one red flag in patient’s brains have continued to lead to disappointing outcomes.

Last Sunday “Sixty Minutes” episode aired on Columbian extended families that inherited a genetic defect that causes early onset Alzheimer’s, by the time they reach 45 years old.

Watching the episode brings to light another case in which a young lady with a different genetic mutation caused her to be afflicted with Alzheimer’s, at the age of 30 years old.

That young lady lost the ability to swallow, causing her to be hooked up to a feeding tube.  She also lost the ability to move her limbs and recognize people.  Dr. Alkon, currently President and Chief Scientific Officer of Neurotrope, (NTRP) was allowed under an FDA compassionate use program to treat the young lady.  She was treated with a drug called bryostatin, which is not a statin, it activates PKC epsilon.  Within a short time she was able to recognize people, extend her arm to reach out to her husband and begin to swallow. This allowed her to be removed from the feeding tube so that she could drink from a straw and eventually regain the ability to speak some words.

The activation of PKC epsilon activates the main amyloid degrading enzymes, ECE, neprilysin, and IDE while activating Alpha Secretase.  Alpha Secretase has been a target for treating Alzheimer’s.  The problem has been finding a safe one.  Eli Lilly’s(LLY) and Biogen’s (BIIB) drugs are monoclonal antibodies that inhibit amyloid beta.  But Lilly’s drug, solanezumab, just failed a major Phase III trial, showing it was no better at slowing down cognitive decline than placebo. Merck (MRK) has a BACE inhibitor that also inhibits amyloid beta.  Neurotrope’s bryostatin, in addition to degrading amyloid, also normalizes GSK3 beta.  That mechanism prevents the hyperphosphorylation of tau.  So you don’t have to be a tauist or a baptist, bryostatin hits both targets.

Incredibly, bryostatin also activates growth factors in the brain, such as BDNF, NGF and IGF-1.  This mechanism causes synaptogenesis.  That allows the brain to restore damaged synapses and grow new synapses. The hope is that the damage caused by Alzheimer’s disease may actually be reversed through this mechanism.

Dr. Alkon didn’t start out by trying to find a drug to fight Alzheimer’s.  He was leading a department at the NIH trying to find out how to increase memory and he came upon PKC epsilon.  PKC epsilon was the conductor in the center of the orchestra, arranging the different mechanisms to create the masterpiece of memory.

Take that, Eli Lilly and Biogen.  You guys have to give your drugs extremely early in the disease, to have any hope of your drugs working, because you need to treat patients before any damage to the synapses has occurred.  So far all those drugs have failed, and the excuse is always that they haven’t been given early enough in the disease process.  If bryostatin can reverse the disease in moderate to severe patients, the drug would be given in all stages.  Perhaps even for prevention in the early onset mutations or APOE4 cases.  Yes, Dr. Alkon even has performed preclinical studies showing that bryostatin can counteract the negative genetic mechanism of the APOE4 gene.

The data that the company will be releasing in five months, April 2017, from their 148 patient Phase II placebo controlled trial.  Multi modal efficacy of bryostatin targeting PKC epsilon, versus everyone else’s drugs, that are just trying to hit one target.  It isn’t even a fair fight. Neurotrope’s bryostatin, if approved, is a blockbuster for one of the largest unmet medical needs in the world today.

Large Integrated Health Outcomes Study Reveals Shifting Epidemiology In Drug-Resistant Organisms

A first-of-its-kind study of 900,000 hospital admissions from an integrated health system has yielded insights into shifts in the epidemiology of multi-drug resistant organisms (MDROs) in the community.

New research, funded by OpGen (NASDAQ: OPGN) and conducted by Intermountain Healthcare and Enterprise Analysis Corporation (EAC), found that Methicillin Resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. difficile) and ESBL harboring Gram-negative rods were the most common organisms treated by the Intermountain Healthcare system over an eight-year period between January 1, 2008 and December 31, 2015.

The study examined data from Intermountain Healthcare over an eight-year period to characterize the trends occurring in C. difficile and MDROs. The abstracted electronic data was pulled from patients seen at Intermountain’s 22 hospitals and affiliated clinics who had clinical cultures positive for antibiotic resistant Gram-positive or Gram-negative bacteria and/or laboratory tests positive for toxigenic C. difficile.

The researchers discovered that resistant organisms were found in 1.4 percent of the 900,000 hospital admissions during the study period with most originating from the ambulatory setting. Additionally, researchers found that a 222% increase was observed in the prevalence of C. difficile as well as a 322% increase in ESBL positive organisms. The good news is that the prevalence of MRSA decreased by 32%.

The study measured both the prevalence of infections, as well as impacts on patient care. Economic data are still being analyzed and will be revealed in a future presentation.

Results from the study were presented on Thursday, Oct. 27 at 1:30 p.m., EDT, in the Poster Hall at IDWeek 2016 in New Orleans by Bert Lopansri, M.D., lead author of the study at Intermountain Medical Center, the flagship hospital of Intermountain Healthcare.

Highlights of the study:

• Of the 900,000 hospital admissions during the study period, 12,905 (1.4%) were from patients positive for an MDRO and/or C. difficile.
• While MRSA continues to be the most common MDRO, rates have declined.
• MRSA, ESBL and CRE forms of E. coli were less frequently acquired in the hospital while VRE, multi-drug resistant Pseudomonas, and other CRE’s were more frequently encountered in a healthcare setting.
• 70% of all MDROs and C. difficile cases originated from an ambulatory setting.
• While all-cause, in hospital mortality was relatively low (7%), significantly more patients with MDRO require continued medical care in some capacity.

“For the last 10 to 15 years, the number of antibiotic-resistant bacteria continues to increase. We wanted to turn on the lights and look at all the different types of antibiotic-resistant bacteria that have been highlighted as serious and urgent threats by the Centers for Disease Control to see what the landscape looks like in our system,” said Dr. Lopansri, Chief of the Infectious Diseases Division at Intermountain Medical Center. “Although MRSA still poses the greatest challenge, the rise in ESBLs is a major concern and mirrors findings reported at other centers in the U.S. One concern with ESBLs is that the most common antibiotic used to treat them are carbapenems, known as ‘last-resort’ antibiotics.”

“Our support for a study of this magnitude provides a benchmark to hospitals and health systems on what could be lurking in their facilities as we seek to validate the health and economic impact of our rapid MDRO products and services to improve infection control,” said Evan Jones, Chairman and CEO of OpGen. “The next step in this collaboration will revolve around leveraging our technologies to guide rapid clinical decisions with a goal of reducing the spread of these infections and improving health outcomes.”

Calcium Supplements May Damage The Heart

After analyzing 10 years of medical tests on more than 2,700 people in a federally funded heart disease study, researchers at Johns Hopkins Medicine and elsewhere conclude that taking calcium in the form of supplements may raise the risk of plaque buildup in arteries and heart damage, although a diet high in calcium-rich foods appears be protective.

In a report on the research, published Oct. 10 in the Journal of the American Heart Association, the researchers caution that their work only documents an association between calcium supplements and atherosclerosis, and does not prove cause and effect.

But they say the results add to growing scientific concerns about the potential harms of supplements, and they urge a consultation with a knowledgeable physician before using calcium supplements. An estimated 43 percent of American adult men and women take a supplement that includes calcium, according the National Institutes of Health.

“When it comes to using vitamin and mineral supplements, particularly calcium supplements being taken for bone health, many Americans think that more is always better,” says Erin Michos, M.D., M.H.S., associate director of preventive cardiology and associate professor of medicine at the Ciccarone Center for the Prevention of Heart Disease at the Johns Hopkins University School of Medicine. “But our study adds to the body of evidence that excess calcium in the form of supplements may harm the heart and vascular system.”

The researchers were motivated to look at the effects of calcium on the heart and vascular system because studies already showed that “ingested calcium supplements — particularly in older people — don’t make it to the skeleton or get completely excreted in the urine, so they must be accumulating in the body’s soft tissues,” says nutritionist John Anderson, Ph.D., professor emeritus of nutrition at the University of North Carolina at Chapel Hill’s Gillings School of Global Public Health and a co-author of the report. Scientists also knew that as a person ages, calcium-based plaque builds up in the body’s main blood vessel, the aorta and other arteries, impeding blood flow and increasing the risk of heart attack.

The investigators looked at detailed information from the Multi-Ethnic Study of Atherosclerosis, a long-running research project funded by the National Heart, Lung, and Blood Institute, which included more than 6,000 people seen at six research universities, including Johns Hopkins. Their study focused on 2,742 of these participants who completed dietary questionnaires and two CT scans spanning 10 years apart.

The participants chosen for this study ranged in age from 45 to 84, and 51 percent were female. Forty-one percent were white, 26 percent were African-American, 22 percent were Hispanic and 12 percent were Chinese. At the study’s onset in 2000, all participants answered a 120-part questionnaire about their dietary habits to determine how much calcium they took in by eating dairy products; leafy greens; calcium-enriched foods, like cereals; and other calcium-rich foods. Separately, the researchers inventoried what drugs and supplements each participant took on a daily basis. The investigators used cardiac CT scans to measure participants’ coronary artery calcium scores, a measure of calcification in the heart’s arteries and a marker of heart disease risk when the score is above zero. Initially, 1,175 participants showed plaque in their heart arteries. The coronary artery calcium tests were repeated 10 years later to assess newly developing or worsening coronary heart disease.

For the analysis, the researchers first split the participants into five groups based on their total calcium intake, including both calcium supplements and dietary calcium. After adjusting the data for age, sex, race, exercise, smoking, income, education, weight, smoking, drinking, blood pressure, blood sugar and family medical history, the researchers separated out 20 percent of participants with the highest total calcium intake, which was greater than 1,400 milligrams of calcium a day. That group was found to be on average 27 percent less likely than the 20 percent of participants with the lowest calcium intake — less than 400 milligrams of daily calcium — to develop heart disease, as indicated by their coronary artery calcium test.

Next, the investigators focused on the differences among those taking in only dietary calcium and those using calcium supplements. Forty-six percent of their study population used calcium supplements.

The researchers again accounted for the same demographic and lifestyle factors that could influence heart disease risk, as in the previous analysis, and found that supplement users showed a 22 percent increased likelihood of having their coronary artery calcium scores rise higher than zero over the decade, indicating development of heart disease.

“There is clearly something different in how the body uses and responds to supplements versus intake through diet that makes it riskier,” says Anderson. “It could be that supplements contain calcium salts, or it could be from taking a large dose all at once that the body is unable to process.”

Among participants with highest dietary intake of calcium — over 1,022 milligrams per day — there was no increase in relative risk of developing heart disease over the 10-year study period.

“Based on this evidence, we can tell our patients that there doesn’t seem to be any harm in eating a heart-healthy diet that includes calcium-rich foods, and it may even be beneficial for the heart,” says Michos. “But patients should really discuss any plan to take calcium supplements with their doctor to sort out a proper dosage or whether they even need them.”

According to the U.S. Centers for Disease Control and Prevention, coronary heart disease kills over 370,000 people each year in the U.S. More than half of women over 60 take calcium supplements — many without the oversight of a physician — because they believe it will reduce their risk of osteoporosis.

Researchers Find Fungus-Fighting Compound in Drug Discovery Center Library

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems.

The research team targeted the switch that allows the fungus Aspergillus fumigatus to survive in iron-deficient conditions like the human body. Specifically, they targeted an enzyme known as SidA, which is essential for the synthesis of molecules called siderophores that are made during infection to steal iron from human proteins.

Furthermore, by performing high-throughput screening in the center’s Drug Discovery Screening Laboratory, they found a compound called Celastrol that blocks the growth of iron-producing organelles in the fungus.

The results were published in the journal ACS Chemical Biology.

“This project shows what an asset the screening lab is to the community,” said Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and director of the screening laboratory. “Without the robots and chemical libraries available at the screening lab, this work would not have been possible. We are very fortunate at Virginia Tech to have this facility.”

Aspergillus fumigatus is common and is typically found in soil and decaying organic matter. Most people are exposed to it daily with little consequence, but it can cause lung damage in people with compromised immune systems, such as organ transplant recipients and people with AIDS or leukemia. The mortality rate of this population, when exposed to the fungus, is more than 50 percent, according to the authors.

“Growing antibiotic resistance is demanding the development of target-directed therapies,” said Julia S. Martin del Campo, a postdoctoral research scientist in Sobrado’s lab. “This approach requires the discovery of enzyme inhibitors that block essential pathogen pathways. The discovery of Celastrol as a SidA inhibitor represents the first building block in the development of drugs against A. fumigatus and related pathogens.”

A New Way to Nip AIDS in the Bud

When new AIDS virus particles bud from an infected cell, an enzyme named protease activates to help the viruses mature and infect more cells. That’s why modern AIDS drugs control the disease by inhibiting protease.

Now, University of Utah researchers found a way to turn protease into a double-edged sword: They showed that if they delay the budding of new HIV particles, protease itself will destroy the virus instead of helping it spread. They say that might lead, in about a decade, to new kinds of AIDS drugs with fewer side effects.

“We could use the power of the protease itself to destroy the virus,” says virologist Saveez Saffarian, an associate professor of physics and astronomy at the University of Utah and senior author of the study released today by PLOS Pathogens, an online journal published by the Public Library of Science.

So-called cocktails or mixtures of protease inhibitors emerged in the 1990s and turned acquired immune deficiency syndrome into a chronic, manageable disease for people who can afford the medicines. But side effects include fat redistribution in the body, diarrhea, nausea, rash, stomach pain, liver toxicity, headache, diabetes and fever.

“They have secondary effects that hurt patients,” says Mourad Bendjennat, a research assistant professor of physics and astronomy and the study’s first author. “And the virus becomes resistant to the inhibitors. That’s why they use cocktails.”

Bendjennat adds that by discovering the molecular mechanism in which protease interacts with HIV, “we are developing a new approach that we believe may be very efficient in treating the spread of HIV.”

However, he and Saffarian emphasize the research is basic, and that it will be a decade before more research might develop the approach into news AIDS treatments.

Figuring out the role of protease in HIV budding

Inside a cell infected by HIV, new virus particles are constructed largely with a protein named Gag. Protease enzymes are incorporated into new viral particles as they are built, and are thought to be activated after the new particles “bud” out of infected cell and then break off from it.

The particles start to bud from the host cell in a saclike container called a vesicle, the neck of which eventually separates from the outer membrane of the infected cell. “Once the particles are released, the proteases are activated and the particles transform into mature HIV, which is infectious,” Saffarian says.

“There is an internal mechanism that dictates activation of the protease, which is not well understood,” he adds. “We found that if we slow the budding process, the protease activates while the HIV particle is still connected to the outer membrane of host [infected] cell. As a result, it chews out all the proteins inside the budding HIV particle, and those essential enzymes and proteins leak back into the host cell. The particle continues to bud out and release from the cell, but it is not infectious anymore because it doesn’t have the enzymes it needs to mature.”

Budding HIV needs ESCRTs

The scientists found they could slow HIV particles from budding out of cells by interfering with how they interact with proteins named ESCRTs (pronounced “escorts”), or “endosomal sorting complexes required for transport.”

ESCRTs are involved in helping pinch off budding HIV particles – essentially cutting them from the infected host cell.

Saffarian says scientific dogma long has held “that messing up the interactions of the virus with ESCRTs results in budding HIV particles permanently getting stuck on the host cell membrane instead of releasing.” Bendjennat says several studies in recent years indicated that the particles do get released, casting some doubt on the long held dogma.

The new study’s significance “is about the molecular mechanism: When the ESCRT machinery is altered, there is production of viruslike particles that are noninfectious,” he says. “This study explains the molecular mechanism of that.”

“We found HIV still releases even when early ESCRT interactions are intentionally compromised, however, with a delay,” Saffarian says. “They are stuck for a while and then they release. And by being stuck for a while, they lose their internal enzymes due to early protease activation and lose their infectivity.”

Bendjennat says by delaying virus budding and speeding “when the protease gets activated, we are now capable of using it to make new released viruses noninfectious”

How the research was done

The experiments used human skin cells grown in tissue culture. It already was known that new HIV particles assemble the same way whether the infected host cell is a skin cell, certain other cells or the T-cell white blood cell infected by the virus to cause AIDS. The experiments involved both live HIV and so-called viruslike particles.

Bendjennat and Saffarian genetically engineered mutant Gag proteins. A single HIV particle is made of some 2,000 Gag proteins and 120 copies of proteins known as Gag-Pol, as well as genetic information in the form of RNA. Pol includes protease, reverse transcriptase and integrase – the proteins HIV uses to replicate.

The mutant Gag proteins were designed to interact abnormally with two different ESCRT proteins, named ALIX and Tsg101.

A new HIV particle normally takes five minutes to release from an infected cell.

When the researchers interfered with ALIX, release was delayed 75 minutes, reducing by half the infectivity of the new virus particle. When the scientists interfered with Tsg101, release was delayed 10 hours and new HIV particles were not infectious.

The scientists also showed that how fast an HIV particle releases from an infected cell depends on how much enzyme cargo it carries in the form of Pol proteins. By interfering with ESCRT proteins during virus-release experiments with viruslike particles made only of Gag protein but none of the normal Pol enzymes, the 75-minute delay shrank to only 20 minutes, and the 10-hour delay shrank to only 50 minutes.

“When the cargo is large, the virus particle needs more help from the ESCRTs to release on a timely fashion,” Saffarian says.

Because HIV carries a large cargo, it depends on ESCRTs to release from an infected cell, so ESCRTs are good targets for drugs to delay release and let HIV proteases leak back into the host cell, making new HIV particles noninfectious, he says.

Bendjennat says other researchers already are looking for drugs to block ESCRT proteins in a way that would prevent the “neck” of the budding HIV particle from pinching off or closing, thus keeping it connected to the infected cell. But he says the same ESCRTs are needed for cell survival, so such drugs would be toxic.

Instead, the new study suggests the right approach is to use low-potency ESCRT-inhibiting drugs that delay HIV release instead of blocking it, rendering it noninfectious with fewer toxic side effects, he adds.

Antibody-Based Drug Helps “Bridge” Leukemia Patients to Curative Treatment

In a randomized Phase III study of the drug inotuzumab ozogamicin, a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.

Inotuzumab ozogamicin, also known as CMC-544, links an antibody that targets CD22, a protein found on the surface of more than 90 percent of ALL cells. Once the drug connects to CD22, the ALL cell draws it inside and dies.

The study, which revealed complete remission rates of nearly 81 percent and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine.

“Forty-one percent of ALL patients in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11 percent we have seen qualify through standard chemotherapy,” said Hagop Kantarjian, M.D., chair of Leukemia. “Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging.”

Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.

Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90 percent. However, many of those patients will relapse and only about 30 to 50 percent will achieve long-term, disease-free survival lasting more than three years.

“Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier, and just 18 to 25 percent in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58 percent, higher than previously reported, possibly due to patients being treated later in the disease course.”

The study reported moderate side effects, the most common being cytopenia, a disorder that reduces blood cell production, and liver toxicity. Funding was provided by Pfizer, Inc.

Hunting for the brain’s opioid addiction switch

New research by Steven Laviolette’s research team at Western University is contributing to a better understanding of the ways opiate-class drugs modify brain circuits to drive the addiction cycle. Using rodent models of opiate addiction, Dr. Laviolette’s research has shown that opiates affect pathways of associative memory formation in multiple ways, both at the level of anatomy (connections between neurons) and at the molecular levels (how molecules inside the brain affect these connections). The identification of these opiate-induced changes offers the best hope for developing more effective pharmacological targets and therapies to prevent or reverse the effect of opiate exposure and addiction. These results were presented at the 10th Annual Canadian Neuroscience Meeting, that took place  in Toronto, Canada.

“Developing more effective opiate addiction treatments will require a change in the way we view the effects of opiates on the brain. Instead of addiction being a chronic, permanent disease, recent evidence is showing that addiction is controlled by molecular switching mechanisms in the brain, that can be turned on or off with the right interventions” says Dr. Steven Laviolette.

Addiction to opiates is spreading and increasing exponentially, and is currently estimated to affect 15.5 million people worldwide. Opiate drugs’ addictive properties are largely due to the ability of this class of drugs to produce powerful memories associated with the intense experience of pleasure and euphoria they cause. Environmental reminders triggering the recall of these memories can cause a relapse, and these memories can be considered the primary driver of the addiction cycle, from chronic use, to withdrawal and then memory-triggered relapse. For decades, clinical and pre-clinical research considered that opiate consumption caused permanent changes in the brain’s reward circuits, resulting in a persistent vulnerability to relapse. However, more recent investigations have shown that opiates induce changes in multiple brain circuits, including reward and memory circuits, and that these changes are not static, but rather that many drug-induced adaptations could be reversed.

“A critical challenge for addiction research is identifying the precise molecular brain changes caused by addictive drugs like heroin or prescription narcotics”, says Dr. Laviolette. “Once we understand this process, we can develop more effective pharmacological interventions to prevent or reverse them”

Among the targets identified by Dr. Laviolette are receptors and other proteins involved in signalling of a neurotransmitter called dopamine. More specifically, his work has shown that dopamine signalling in two connected brain regions involved in opiate-related memory processing, called the Basolateral Amygdala (BLA), a region deep within the brain, and the medial prefrontal cortex (mPFC), located near the surface of the brain, is switched by opiate exposure. His research shows that in animals that are opiate naïve, never previously exposed to opiates, the reward memory associated with opiates requires a dopamine receptor called D1R in the BLA, and a signalling molecule called extracellular signal-related kinase 1/2 (ERK1/2). Following chronic opiate exposure, however, opiate reward memory formation becomes independent of D1R, and rather depends on a second dopamine receptor, called D2r, and a protein called CaMKII. As CaMKII expression has been associated with consolidation and permanence of memories in other brain regions, this switch may reflect the formation of a stronger and more stable opiate reward memory.

Interestingly, when Dr. Laviolette’s team looked at dopamine signaling inside another brain region also involved in opiate related memory procession, and located closer to the surface of the brain, the mPFC, they found that this signaling was also switched by opiate exposure, but opposite to what was observed in the BLA. In the mPFC, opiate naïve signaling requires CaMKII, while it did not in opiate habituated animals.

Taken together, these results highlight the precise changes and adaptations that occur in the brain following opiate exposure and development of addiction. New pharmacological approaches to target these changes will provide much needed and more effective treatments to reduce the power of drug-related associative memories that drive opiate addiction.

New Study Shows Common NSAIDs can cause more Harm than Good

Many patients around the world, are prescribed non-steroidal anti-inflammatory drugs (called NSAIDs) for the treatment of painful conditions, fever and inflammation. But the treatment also comes with side effects, including the risk of ulcers and increased blood pressure. A major new study from Denmark complied new research that demonstrated that a common arthritis medicine is particularly dangerous for heart patients.

The study also uncovered that older types of arthritis medicine, which have not previously been in focus, also appear to be dangerous for the heart. The study, which was carried out in collaboration between 14 European universities and hospitals, including a number of leading European heart specialists, was published in the most prestigious European journal of heart medicine, European Heart Journal.

“It’s been well-known for a number of years that newer types of NSAIDs – what are known as COX-2 inhibitors, increase the risk of heart attacks. For this reason, a number of these newer types of NSAIDs have been taken off the market again. We can now see that some of the older NSAID types, particularly Diclofenac, are also associated with an increased risk of heart attack and apparently to the same extent as several of the types that were taken off the market,” says Morten Schmidt, MD and PhD from Aarhus University, who is in charge of the research project.

Global Issue Around the World

Pain medications for osteoarthritis account for billions of dollars in annual sales globally. Most pain medications for osteoarthritis, including celecoxib which had global sales of $2.7 billion in 2014, are NSAIDs which have the side effect of elevating blood pressure, and increasing the risk of heart attacks, strokes and death. Of the 27 million Americans who live with osteoarthritis, 13.5 million also suffer from hypertension, which also increases the risk of heart attack, stroke, and death.

Late last year, a new NSAID candidate KIT-302 from Kitov Pharmaceuticals showed good promise as a combination pill that simultaneously treats joint pain and elevated levels of blood pressure. Kitov’s NSAID is a combination of celecoxib and the calcium channel blocker amlodipine.  In Kitov’s phase 3 study, this combination was documented to lower blood pressure better than amlodipine alone, thus enhancing the cardiovascular safety of the amlodipine. In contrast, and consistent with multiple prior publications, celecoxib alone raised blood pressure: An effect that correlates with an increased adverse cardiovascular event rate.

“The primary efficacy of the trial was to show that a combination of the two components of KIT-302, lowers daytime systolic blood pressure by at least 50 percent. Recognizing the cardiovascular dangers associated with NSAID use, Kitov has been working to bring a safer NSAID to market for the past three years,” explained Kitov’s Chairman and Chief Medical Officer, Dr, Paul Waymack.

“Many European countries consume more of these drugs than Denmark. But we can still do better and it’s often the case that paracetamol, physiotherapy, mild opioids or other types of NSAIDs with less risk for the heart would be better for the patients. Of course, the recommendations that have been introduced following our study and its review of the heart-related risks are a big step in the right direction in relation to patient safety,” says Morten Schmidt.