Long-acting drug effectively prevents HIV-like infection in monkeys

The new drug cabotegravir (in vials above) has been shown to protect monkeys from infection by an HIV-like virus, and a clinical trial testing cabotegravir's safety and acceptability has begun. Unlike other preventive treatments, it would require only one injection every three months.
Credit: Zach Veilleux / The Rockefeller University

A regime of anti-HIV drugs -- components of regimens to treat established HIV infection -- has the potential to protect against infection in the first place. But real life can interfere; the effectiveness of this prophylactic approach declines if the medications aren't taken as prescribed.

HIV researchers hope a new compound, known as cabotegravir, could make dosing easier for some because the drug would be administered by injection once every three months. A clinical trial testing long-acting cabotegravir's safety and acceptability has already begun at multiple U.S. sites including The Rockefeller University Hospital. Meanwhile two new studies, including one conducted by researchers at the Aaron Diamond AIDS Research Center (ADARC) and Rockefeller University, published today (January 15) in Science Translational Medicine, show that long-acting cabotegravir injections are highly protective in a monkey model of vaginal transmission of a virus similar to HIV.

"Clinical trial results have demonstrated that the effectiveness of preventive oral medications can range with results as high as 75 percent effective to as low as ineffective, and a lot of that variability appears to hinge on the patient's ability to take the pills as prescribed," says study researcher Martin Markowitz, a professor at Rockefeller University and ADARC. "Long acting cabotegravir has the potential to create an option that could improve adherence by making it possible to receive the drug by injection once every three months."

Developed by ViiV Healthcare and GlaxoSmithKline, and previously known as GSK744 LA, cabotegravir is an antiretroviral drug. Antiretrovirals interfere with HIV's ability to replicate itself using a host cell and they are used to treat an HIV infection or to prevent those at high risk from acquiring it in the first place.

Cabotegravir belongs to a group of antiretrovirals that target integrase, an enzyme the virus uses to integrate itself into the cell's genome. This compound is a relative of an already FDA-approved integrase inhibitor, dolutegravir, but with chemical properties that allow it to be formulated into a long-acting suspension for injection.

A previous study by the ADARC and Rockefeller team in collaboration with ViiV Healthcare and GSK found long-acting cabotegravir could protect male rhesus macaque monkeys from exposure to a virus related to HIV. Following up on these results, a phase 2 clinical trial is now underway in a group of 120 men at low risk of infection. Before cabotegravir's effectiveness in high risk individuals can be tested, trials must show that study participants tolerate the drug well and find the quarterly injections, which are a novel approach to HIV prevention, acceptable.

Both new animal studies were conducted with women in mind; in 2013 women accounted for 47 percent of new HIV infections worldwide according to the Joint United Nations Programme on HIV and AIDS. Working separately, two teams tested the drug's ability to block vaginal transmission in two species of monkeys with different breeding cycles and susceptibility to infection.

First author Chasity Andrews, a postdoctoral fellow at ADARC and Rockefeller, and colleagues at ADARC, the Tulane Regional Primate Center and ViiV/GSK, studied female rhesus macaques treated with progesterone to increase their susceptibility to the virus. They found injections of long acting cabotegravir were 90 percent effective at protecting the monkeys from repeated high-dose exposures to the virus.

Meanwhile, the complementary study conducted by researchers at the CDC and ViiV/GSK found female pigtail macaques injected with cabotegravir were completely protected against multiple exposures to the virus.

"While we are still a long way off from showing that this drug works for HIV prevention in humans, our hope is that it may one day offer high risk women, as well as men, an additional option for HIV prevention," Markowitz says. "One of the lessons we have learned from contraception is the more options available, the better. We are hoping for the same in HIV prevention -- more options and better results."

Source: Rockefeller University

Read More

Special delivery: Hitchhiking microparticles deliver drugs directly

Disc-shaped microparticles use monocytes to get to their destination. Credit: Peter Allen illustration

Inflammation is a normal and often beneficial response to injury or infection. The swelling, heat and even pain are the body's attempts to protect its soft tissue, remove offending objects, substances or microbes and initiate healing. However, persistent inflammation is often indicative of more serious conditions and can lead to problems of its own, including impaired healing, loss of function or even tissue death.

"Many diseases result in inflammation," said Samir Mitragotri, professor of chemical engineering at UC Santa Barbara and director of the campus's Center for Bioengineering. Whether inflammation is a byproduct of the disease or the inflammation is the disease, it is a common indicator of a problem with the system. "If we could target the common denominator, whether the inflammation is coming from cancer or arthritis, we could deliver the drug there," said Mitragotri, who specializes in targeted drug delivery.

By taking advantage of natural body processes, researchers at UC Santa Barbara and MIT have developed a method of targeting inflamed tissues, creating a way to treat both the inflammation and its underlying cause.

"It's a cell-mediated approach to targeted drug delivery," said UCSB grad student researcher Aaron Anselmo, lead author of a study in the current issue of the Journal of Controlled Release.

Key to this technology is the utilization of monocytes, the type of white blood cell known for its ability to penetrate into deep sections of tissue. Under normal circumstances, the job of these monocytes is to circulate in the blood and respond to biochemical signals that indicate inflammation -- a sign of injury or infection. Once at the site, these monocytes transform into macrophages, cells that reside in the affected tissues to engulf and digest foreign material.

Working with the expertise of chemical engineering and materials science researchers at MIT, including graduate researcher Jonathan Gilbert and professors Robert Cohen and Michael Rubner, the UCSB researchers developed an approach based on "cellular backpacks" -- flat, disc-shaped polymeric particles that could, in the near future, hold therapeutic agents that can be released at the site of the inflammation. These polymeric discs are coated on one side with a single layer of an antibody that can bind to receptors on the monocyte's surface.

To prevent the cellular backpack from being engulfed and devoured by the very cell that is transporting it, the researchers chose a flexible particle that is nonspherical in shape, which, according to the study, has proved to be more durable and resistant to phagocytosis than a rigid spherical particle. The shape and flexibility gives the backpack the ability to bind strongly while resisting phagocytosis to hitchhike onto monocytes and reach the inflamed tissue.

In-vitro and in-vivo tests have proved that cellular backpacks are successful in attaching to and being transported by monocytes to target areas without impairing the monocytes' natural functions, said Anselmo. Further studies will include research into how much drug can be loaded into the cellular backpacks. Ideally, Anselmo said, the cellular backpacks loaded with drugs would be injected into the bloodstream, whereupon they would attach to these traveling monocytes and hitchhike to the target region. At the inflamed site, the particles would simultaneously degrade and release their drugs.

The development of effective cellular backpacks has broad potential, say the researchers.
"Basically the main benefit is that you can deliver the drug in a more effective dose," Mitragotri said. Take for example the case of chemotherapy, which often has a narrow therapeutic range: Too little and the treatment is not effective, too much and it can be lethal. 
Because chemo travels through the bloodstream and affects all the tissues it comes in contact with, dosages are restricted at least in part based on the deleterious effect it has on other, unafflicted organs and their functions. Not only can targeted therapy ensure other body systems remain unaffected, Mitragotri explained, but it could allow for higher doses of drug to the site, which could decrease treatment time.

Source: University of California - Santa Barbara

Read More

How to sell the drugs of the future

Drugs
Credit: Getty Images

Only a decade ago, basing medical treatment on your DNA seemed like science fiction. Not any more. Thanks in part to the sequencing of the human genome, personalized medicine (PM), a specific course of treatment developed for the individual patient, is now science fact.

PM has already shown its effectiveness in the treatment of cancer, and medical professionals are eager to expand it to treat other chronic diseases. But first patients need to understand how PM can work for them.

Will they buy into it? "Yes -- but only if patients are armed with knowledge about their own disease and understand the relative advantages of PM," says Concordia University marketing professor Lea Prevel Katsanis, the co-author of a new study on the subject, published in the International Journal of Pharmaceutical and Healthcare Marketing. She adds that if patients are going to accept PM, doctor-patient communication is vital.

For the study, Katsanis and her co-author, Anja Hitz, a former John Molson School of Business MBA student and current head of medical compliance and prevention at the Military Hospital in Hamburg, Germany, polled 307 consumers through an online survey. 
They found that knowledge and the relative advantages of PM have the most significant influence on patient acceptance of PM.

"The more a patient knows about how she is being treated, the more likely she is to accept that treatment," says Katsanis. "So it's important to educate consumers on potential benefits and risks associated with PM."

Indeed, patient understanding is a key factor in getting healthcare professionals, governments and insurance companies to adopt and pay for PM, particularly when these targeted treatments are often more costly than traditional medical methods.

With PM, the same drug isn't given to millions of people. It's a targeted treatment regime. While that reduced patient pool means an increased cost, there can be long-term benefits. Increased efficiency and prevention may result in fewer drugs being prescribed. And PM may also result in the reduction of secondary costs as a result of overdosing, incorrect prescriptions and adverse drug reactions.

"If PM can be successfully integrated into the healthcare system at a reasonable cost, it represent a significant improvement in the treatment of chronic disease," says Katsanis.

But she warns that marketers need to proceed with caution: "The promotion of personalized medications will increasingly focus on the healthy patient with a genetic disposition for a particular illness. While this might lead to new and potentially greater opportunities for marketers, it might also result in the targeting of healthy patients who don't actually need treatment for an active disease. Ultimately, this could increase healthcare costs and cause unnecessary patient treatment."

Source: Concordia University

Read More

A lab in your pocket: Using CAD to load dozens of tests on a lab-on-a-chip

Two computer-generated configurations for routing a droplet through multiple lab-on-a-chip diagnostic tests, many more than are currently possible using manual methods. The software was developed by Michigan Tech's Shiyan Hu and Chen Liao. The figure is reproduced with permission of IEEE Transactions on NanoBioscience. Credit: Chen Liao and Shiyan Hu

When you get sick, your physician may take a sample of your blood, send it to the lab and wait for results. In the near future, however, doctors may be able to run those tests almost instantly on a piece of plastic about the size of credit card.

These labs-on-a-chip would not only be quick -- results are available in minutes -- but also inexpensive and portable. They could be used miles from the nearest medical clinic to test for anything from HIV to diabetes. But as powerful as they may be, they could be far better, says Shiyan Hu, an associate professor of electrical and computer engineering at Michigan Technological University.

Generally, a lab-on-a-chip (LOC) can run no more than a test or two. That's because the chips are designed manually, says Hu. If the LOC were made using computer-aided design, you could run dozens of tests with a single drop of blood.

"In a very short time, you could test for many conditions," he said. "This really would be an entire lab on a chip."

With PhD student Chen Liao, Hu has taken the first step. "We have developed software to design the hardware," he said. Their work focuses on routing the droplet of blood or other fluid through each test on the chip efficiently while avoiding any chip contamination.

"It has taken us four years to do the software, but to manufacture the LOC would be inexpensive," Hu said. "The materials are very cheap, and the results are more accurate than a conventional lab's."

Ultimately, Hu aims to fabricate their own biochip using their software.

Their work was featured on the cover of the March edition of IEEE Transactions on Nanobiosciences and described in the article "Physical-Level Synthesis for Digital Lab-On-a-Chip Considering Variation, Contamination, and Defect." Liao was partially supported by an A. Richard Newton Graduate Scholarship, awarded by the Design Automation Conference.

Source: Michigan Technological University

Read More

‘Smart’ drugs won’t make smart people smarter, research concludes

Dr. Ahmed Dahir Mohamed is in the School of Psychology at The University of Nottingham Malaysia Campus. Credit: The University of Nottingham

The study carried out by Dr Ahmed Dahir Mohamed, in the School of Psychology at The University of Nottingham Malaysia Campus, and published in the open access journal PLOS ONE, showed the drug had negative effects in healthy people.

Dr Mohamed said: "We looked at how the drug acted when you are required to respond accurately and in a timely manner. Our findings were completely opposite to the results we expected."

In a randomised double blind study, 'Modafinil increases the latency of response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial', they administered 32 participants with the drug and 32 with a placebo. All the participants were given a famous neuropsychological task known as the Hayling Sentence Completion Test in which they were asked to respond both quickly and accurately. Dr Mohamed found the drug slowed down reaction times, impaired their ability to respond in a timely manner and failed to improve their performance of the task.

Dr Mohamed said: "It has been argued that Modafinil might improve your performance by delaying your ability to respond. It has been suggested this 'delay dependent improvement' might improve cognitive performance by making people less impulsive. We found no evidence to support those claims.

"Our research showed that when a task required instant reactions the drug just increased reaction times with no improvement to cognitive performance."

This backs up the findings of a previous study carried out by Dr Mohamed and published in September 2014 in The Journal of Creative Behaviour. The study: The Effects of Modafinil on Convergent and Divergent Thinking of Creativity: A Randomised Controlled Trial showed that the so called 'smart' drug impaired the participant's ability to respond in a creative way particularly when they were asked to respond laterally -- outside the box.

Does Modafinil benefit anyone?

When Dr Mohamed looked at participant's ability to problem solve in a creative manner he found that those who weren't particularly creative to start with were improved by the drug while those who were creative were impaired by the drug. He said: "Our study backs up previous research that suggests psychostimulants improve people at the lower end of the spectrum in cognition whereas they impair people who are at the optimum level of cognitive function -- healthy people for example. It looks like Modafinil is not helpful for healthy individuals and it might even impair their ability to respond and might stifle their lateral thinking, while people who have some sort of deficiency in creativity are helped by the drug."

What can make us smarter?

Ahmed Mohamed's research was carried out while he was at Cambridge University. He has since moved to The University of Nottingham Malaysia Campus where he will be looking at the effects of non-pharmacological interventions, such as meditation, exercise and diet on the healthy brain. He is also currently using Electroencephalography (EEG) to study how mindfulness can affect the healthy adolescent brain.

Dr Mohamed said: "What I have found in my doctoral studies is that if you are already a healthy person and functioning at an optimum level, it is really difficult to improve your cognition. But the brain of the adolescent is still in development and you might be able to improve cognition at this stage of our development through positive interaction, healthy diet or mindfulness."

Source: University of Nottingham

Read More

New molecules to burst malaria's bubble

Dr Natalie Spillman. Credit: Alex Maier

Scientists have released details of a raft of new chemicals with potent anti-malarial properties which could open the way to new drugs to fight the disease.

A new paper in PNAS is the third published recently by a group at the Australian National University (ANU). The group has collaborated with scientists from around the globe to uncover potential ammunition in the fight against malaria.

Over 200 million people contract malaria each year, and the parasite that causes the disease has become resistant to most of the drugs currently available.

"The series of papers shows that the malaria parasite has a real Achilles heel, and describe a range of new ways to attack it," said Professor Kiaran Kirk, Dean of the College of Medicine, 
Biology and Environment and one of the scientists involved in the project.

Dr Natalie Spillman, from the Research School of Biology at ANU studied the mechanism by which the parasites are killed.

"The new molecules block a molecular salt pump at the surface of the parasite, causing it to fill up with salt," Dr Spillman said

"This has the effect of drawing water into the parasite, causing it to swell uncontrollably and burst."

Although the process of developing the new compounds into clinical drugs is complex and lengthy, Professor Kirk is optimistic the findings will lead to new treatments.

"It's very early days, but these pump-blocking compounds have some of the most promising anti-malarial potential we've seen," he says.

Aspects of the work were carried out with groups at Griffith University, Monash University and the Menzies School of Health Research in Darwin.

"This is a good example of a long-term, international drug development program in which Australian groups have played a key role," he said.

Source: Australian National University

Read More

Drugs in the environment affect plant growth

Lettuce plants (stock image). The potential for some chemicals to influence plants is becoming increasingly relevant, particularly as waste management systems are unable to remove many compounds from our sewage. Drugs for human use make their way into soil through a number of routes, including the use of sewage sludge as fertilizer and waste water for irrigation.
Credit: © riderfoot / Fotolia

By assessing the impacts of a range of non-steroidal anti-inflammatory drugs, the research has shown that the growth of edible crops can be affected by these chemicals -- even at the very low concentrations found in the environment.

Published in the Journal of Ecotoxicology and Environmental Safety, the research focused its analysis on lettuce and radish plants and tested the effects of several commonly prescribed drugs, including diclofenac and ibuprofen. These drugs are among the most common and widely used group of pharmaceuticals, with more than 30 million prescribed across the world every day.

The potential for these chemicals to influence plants is becoming increasingly relevant, particularly as waste management systems are unable to remove many compounds from our sewage. Drugs for human use make their way into soil through a number of routes, including the use of sewage sludge as fertilizer and waste water for irrigation.

This study looked for a number of changes in edible plants, assessing factors such as water content, root and shoot length, overall size and how effectively the plants photosynthesised.

Each drug was shown to affect the plants in very specific ways, with marked differences between drugs that are closely related. For example, drugs from the fenamic acid class affected the growth of radish roots, whilst ibuprofen had a significant influence on the early root development of lettuce plants.

Dr Clare Redshaw, one of the scientists leading the project at the Medical School's European Centre for Environment & Human Health, said: "The huge amounts of pharmaceuticals we use ultimately end up in the environment, yet we know very little about their effects on flora and fauna. As populations age and generic medicines become readily available, pharmaceutical use will rise dramatically and it's essential we take steps towards limiting environmental contamination. We haven't considered the impact on human health in this study, but we need to improve our understanding quickly so that appropriate testing and controls can be put in place."

There have been growing concerns about the presence of pharmaceuticals in the environment, particularly as evidence emerges of the effects they can have on the development of animals and antibiotic resistance in bacteria. Yet their ability to affect plant growth is poorly understood.

This study marks an important step in an emerging research field attempting to assess how very low concentrations of drugs can affect the growth of crucial crop plants. It specifically considered the non-steroidal anti-inflammatory drugs tolfenamic acid, meclofenamic acid, mefenamic acid, diclofenac, naproxen and ibuprofen.

Source: University of Exeter

Read More