Brain Blogger » Drugs & Clinical Trials http://brainblogger.com Health and Science Blog Covering Brain Topics Tue, 25 Nov 2014 12:00:36 +0000 en-US hourly 1 http://wordpress.org/?v=4.0.1 Memory Enhancement – Nootropics and Electromagnetic Stimulation http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/ http://brainblogger.com/2014/11/18/memory-enhancement-nootropics-and-electromagnetic-stimulation/#comments Tue, 18 Nov 2014 12:00:21 +0000 http://brainblogger.com/?p=17379 Memories naturally degrade with the passing of time. Although the information is initially registered and stored, after a couple of days, weeks, or even years, it is simply erased from storage. The decline of memory function, be it due to normal aging or due to specific medical conditions, greatly affects one’s day-to-day life. Consequently, it is no surprise that the search for ways of improving memory has thousands of years of history.

The vast majority of the retrieval processes (i.e. most of remembering) happens without us even realizing. It is automatic and requires little to no effort or planning. Interestingly, the information that our subconscious identifies as being important or truly relevant tends to be kept in storage for as long as we need it. This can range from a transient need, like the information that you studied for a school exam, to a permanent, primary need, like recognizing your family’s faces and names.

Memory improvement strategies that have been employed throughout the centuries range from simple cognitive exercises and diet modifications to actual pharmaceutical products which influence the molecular pathways at play in memory processes. While many of these strategies have failed to produce any desirable effects, some substances have actually provided with interesting results in different settings.

Nootropics

Nootropics are a group of such substances which show evidence of positively affecting one or more aspects of memory functions. These substances includes not only drugs, but also supplements, “nutraceuticals”, and functional foods.

Notwithstanding the diversity of nootropic compounds, it is possible to summarize their mechanisms of action as follows:

  • increasing circulation to the brain
  • providing precursors to neurotransmitters
  • improving neuronal function
  • preventing oxidative neuronal damage
  • providing energy sources to the brain.

Perhaps the most famous type of nootropics are racetams, which include various structurally similar compounds, such as piracetam and oxiracetam. Little is known about their precise actions at the molecular level, but there are a few clinical studies indicating their potential when prescribed to individuals with specific memory problems.

For instances, in a study of oxiracetam therapy in patients with senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID) of mild to moderate degree, significant improvements were observed. Nootropics are also very popular for being available over-the-counter and for having virtually no undesirable side effects.

Dietary supplements, such as vitamins and omega-3, are considered nootropics as well, thanks to their influence on memory, learning, concentration and decision-making.

Other popular classes of nootropics include:

  • stimulants, such as amphetamines and xanthines (e.g. caffeine)
  • dopaminergics, affecting the neurotransmitter dopamine or the components of the nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention, alertness, and antioxidant activity
  • cholinergics, including acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors
  • nutraceuticals, including Bacopa monnieri, isoflavones and Gingko biloba.

One of the nootropic substances that has sparked a lot of scientific curiosity is nicotine. Famously known for its carcinogenic potential and a myriad of other adverse effects on smokers’ health, researchers have long been aware of the ability of nicotine to influence cognitive performance.

For example, difficulty in concentrating is one of the symptoms of nicotine withdrawal, but for a long time this was regarded as a mere relapse factor. Still, as smokers repeatedly reported that one of the reasons they smoke is for the perceived cognitive improvement that smoking gives them, experiments have been attempting, for more than 40 years, to validate these claims and to delineate the conditions under which nicotine might enhance the various domains of human performance.

Biologically, there is a basis for the influence of nicotine in cognitive processes. Nicotine binds to presynaptic nicotinic acetylcholine receptors in the brain, facilitating the release of acetylcholine, dopamine, serotonin, glutamate, and other neurotransmitters known to be involved in these processes.

A meta-analysis of the acute and long-term effects of nicotine on human performance, which looked at the results of a number of studies on the topic, revealed impressive results. Nicotine appears to actually have a significant, positive impact on six domains: fine motor, alerting attention-accuracy, response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT.

Despite these positive effects, it is important to stress that nicotine should not be the nootropic of choice for anyone seeking to improve their memory functions, due to the numerous medical issues it potentiates and the dependence it causes.

As one would expect, like all pharmaceutical products, nootropics have risks as well as benefits. Most of these enhancers are being used with little scientific data to support them, and while some compounds are known to have a good safety profile, others have a risk of unintended side effects that is both high and consequential. It is also important to stress that having an acceptable safety profile is actually dependent on the circumstances under which the product is administered. For example, a drug that restored good cognitive functioning to people with severe dementia but caused serious adverse medical events might be deemed reasonable to prescribe to these patients under the light of its great benefits, but not to healthy individuals who are only seeking enhancement.

Even in terms of practical efficacy, there is much to be said about nootropics. Despite the fact that some studies have shown impressive results, the truth is that there is a lot of heterogeneity (not to mention transiency) in response.

But science is an ever moving field, and recent studies have provided some insight into what might be a revolution in the area of cognitive enhancement. A groundbreaking investigation, published just this year in the renowned journal Science, suggests that there might be a more effective, alternative strategy to stimulate and improve the processes underlying memory formation.

Electromagnetic stimulation

We have known for quite some time now, mainly in the aftermath of very select cases of severe brain injuries which are illuminating by virtue of the impairments they produce, that the hippocampus plays a decisive role in the works of memory. Naturally, the hippocampus does not work on its own, and a team of American researchers took advantage of these complex interactions to test its function.

Using the technique of noninvasive electromagnetic stimulation – never tested in humans before – researchers altered the interactions between the networks of hippocampal and cortical neurons and registered the effects of such modulation on memory. After multiple sessions of electromagnetic stimulation, there was a clear functional increase in the transmission of neural impulses between those neurons. Concomitantly, associate memory performance of the subjects involved improved significantly, persisting about 24 hours after stimulation.

While these results are promising and may constitute a new window into the mechanics of memory formation and memory enhancement, they are also preliminary findings that still leave many questions unanswered. Further investigations, both in healthy individuals and in people with medical issues associated with memory formation, will be necessary for the scientific community to really understand the benefits and risks of electromagnetic stimulation.

References

Greely, H. (2013). Some First Steps Toward Responsible Use of Cognitive-Enhancing Drugs by the Healthy The American Journal of Bioethics, 13 (7), 39-41 DOI: 10.1080/15265161.2013.795823

Gruneberg, M. and Morris, P.E. (1994). Theoretical Aspects of Memory, Volume 2, Routledge.

Heishman SJ, Kleykamp BA, & Singleton EG (2010). Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology, 210 (4), 453-69 PMID: 20414766

Rosenbaum RS, Gilboa A, & Moscovitch M (2014). Case studies continue to illuminate the cognitive neuroscience of memory. Annals of the New York Academy of Sciences, 1316, 105-33 PMID: 24871381

Villardita C, Grioli S, Lomeo C, Cattaneo C, & Parini J (1992). Clinical studies with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia of mild to moderate degree. Neuropsychobiology, 25 (1), 24-8 PMID: 1603291

Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, & Voss JL (2014). Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science (New York, N.Y.), 345 (6200), 1054-7 PMID: 25170153

Image via Africa Studio / Shutterstock.

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Why Are We Still Developing Brain Drugs? http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/ http://brainblogger.com/2014/02/11/why-are-we-still-developing-brain-drugs/#comments Tue, 11 Feb 2014 12:00:59 +0000 http://brainblogger.com/?p=15909 The social stigma surrounding the pharmaceutical industry has gotten pretty bad lately. The business of saving lives is now rated positively by only 32% of the public, tucked neatly between oil and banking in consumer confidence polls – down eight places since 1996. Without dwelling too much into the reasons for pharma’s tumbling social status, one can sense an undeniable skepticism surrounding the intentions of the industry, and, most frighteningly, the effectiveness of its drugs.

It would be bitterly unfair to agree with the hardline pharma critics in that drugs simply do not work. After all, antibiotics, HIV retrovirals, chemotherapy and heart disease drugs continue to attest to just the opposite. Survival prognosis for infection, atherosclerosis or even cancer is so great today, that 95% more people reach the age of 80 than they did a century ago.

But with longer-living populations come older-age diseases, and the therapeutic landscape begins to dramatically shift towards diseases like dementia, Alzheimer’s and Parkinson’s, and diseases which have remained poorly treated, such as schizophrenia, bipolar disorder and depression.

Brain Drugs: 50 years later, we still can’t tell you how they work

Note that the common denominator of all “modern” disorders is that they are all diseases of the brain. These ailments bear an economic burden of more than $2 trillion in the US and EU and rake in upwards of $80 billion a year for the pharmaceutical industry.

But nearly all brain medications have come about serendipitously — through observation that certain chemicals improved certain symptoms, rather than through research tailored to the disease. An overwhelming majority of today’s Thorazines, Valiums, Prozacs and Xanaxes are still characterized by widely unknown mechanisms of action 60 years after their market debuts. Even more frighteningly, in recent clinical trial re-runs involving Prozac and Xanax the drugs fared hardly better than placebo.

Is Big Pharma shying away from CNS drugs?

Because the brain remains so poorly understood, Big Pharma are having a bad time developing pharmaceuticals which act upon the central nervous system (CNS). After a number of very loud and painful CNS clinical trial failures in recent years, GSK, AstraZeneca and Novartis have announced total closures of neuroscience divisions globally. Meanwhile Pfizer, Sanofi, Janssen and Merck have begun to significantly downsize CNS operations.

Few remain in the race. And who can blame them, when CNS drug development can cost billions more than any other therapeutic area, yet has a 45% higher chance of failure than drugs targeting other disorders?

Electricity and chemistry rule the brain in equal measure

The complexity of the brain is unrivaled. The intricate network of neuronal connections (the “connectome”), the densely populated molecular environment, and the electric behavior of brain cells, all in addition to the vast individual genomics and metabolomics of any given brain are difficult to ponder even in a single sentence. Unlike the peripheral nervous system, where molecules govern tissues, the central nervous system is just as much ruled by the binary patterns of electrical stimulation as by the neurotransmitter molecules which carry brain messages throughout the body.

And this is the crucial point: chemicals and electricity share a 50:50 responsibility in the brain. A chemical release between two neurons will cause the downstream neuron to “electrically detonate”, sending the message forward, yet electric stimulation of the upstream neuron will succeed to do just the same, albeit without collateral damage to much of the neuronal neighborhood (chemicals spread multridirectionally, whilst electricity does not).

The future is electric

Scientists have known of the effectiveness of neuro-electric brain therapy for decades, and many such systems are already in use today. Deep Transcranial Magnetic Stimulation (Deep TMS), for instance, is a novel, non-invasive, FDA-approved therapy to-date found effective for the treatment of Parkinson’s disease, depression, chronic pain and schizophrenia.

Deep TMS involves magneto-electric activation of regions deep (up to 7cm) within the brain. The stimulation can be applied at virtually any 3D brain coordinates. Thus the more we map the brain, the more useful the treatment becomes.

Pill lovers needn’t get disheartened by the prospect of an electric future, either. Meticulous brain mapping and advances in drug delivery systems could potentially culminate in the birth of a highly lucrative pharmaceutical — the electroceutical — or, rather more bluntly, electricity in a pill.

Electroceuticals may eventually take the form of electro-charged nano-robots we ingest in a pill, which would, with military precision, deliver electric current to any desired brain coordinates. In the era of electroceuticals, chemical “cross-contamination” of tissues and brain areas, along with unwanted side effects and liver toxicity would become a figment of the past.

How close are we to the electric future?

An often surprising fact is that electric therapy is already very widely used in the hospital, even in what would be considered traditional surgical settings. According to Itzhak Fried — Israel’s leading brain surgeon famed for his 22-hour separation surgery on Siamese twins literally sharing a brain — many procedures performed at his department already require an electric element.

In a breakthrough surgery two years ago, Fried’s team implanted tiny electrodes into the brain of an epilepsy patient. The electrodes, much like a tape recorder, listened to and recorded the activity of neurons in an area suspected of generating seizures. The “playback” of the recorded cell activity then gave clues as to the exact location of where the seizures originated. This turned out to be a tiny brain area next to the speech center of the brain which then was safely and successfully excised. Just a millimeter in the wrong direction could have rendered the patient forever unable to speak. All hail electricity.

Obama thinks the future is electric, too

And here is why all the electricity talk is not just cuckoo clairvoyance. Firstly, there is an unmissable brain project frenzy scurrying across the world. Projects like the “Brain Research through Advancing Innovative Neurotechnologies” (BRAIN), initiated by President Obama in the U.S., The Human Brain Project in Europe and Israel Brain Technologies are all aimed at electrically mapping the brain. Some lab projects have gone so far as to make mouse skulls completely transparent or to implant fiber optics into rat brains.

An equally telling development is the injection (or diversion from previous CNS research and development) of funds into electroceutical research done by Big Pharma themselves. In August 2013, GSK unveiled a $50 million bioelectrics venture fund aimed at sponsoring projects “that begin detailing how nerves in the body are related to particular diseases, understand the firing patterns of those nerves, and explore new technologies that will enable us to interface with multiple individual nerve fibres”. As CNS departments are ubiquitously shutting down, other players are left with no choice but to shortly follow suit.

It certainly seems that there is one thing neurosurgeons, neuroscientists and Big Pharma all finally agree on: neuro-chemistry is just so 2004.

Image via Palau / Shutterstock.

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Ambien Zombies, Murder, and Other Disturbing Behavior http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/ http://brainblogger.com/2014/01/25/ambien-zombies-murder-and-other-disturbing-behavior-2/#comments Sat, 25 Jan 2014 21:12:23 +0000 http://brainblogger.com/?p=15821 Ambien is one of a number of Controlled Schedule 4 agents designed as sedative hypnotics. Like other sedative hypnotics they are usually effective for about two weeks, largely to relieve persisting insomnia. These agents, especially Ambien, are linked to sleep-driving, eating, and even sex.

Sedative hypnotics impact mostly the neurotransmitter, GABA, which is inhibitory in its psychokinetic impact. As with other psychotropics, there is a darker side of the experience, though rare.

On March 29, 2009, Robert Stewart, 45, stormed into the Pinelake Health and Rehab nursing home in Carthage, North Carolina and opened fire, killing eight people and wounding two. Stewart’s apparent target was his estranged wife, who worked as a nurse in the home. She hid in a bathroom and was unharmed.

Stewart was charged with eight counts of first-degree murder; if convicted, he could face the death penalty. Even though there was evidence that Stewart’s actions were premeditated (he allegedly had a target), Stewart’s defense team successfully argued that since he was under the influence of Ambien, a sleep aid, at the time of the shooting, he was not in control of his actions. Instead of the charges sought by the prosecutors, Stewart was convicted on eight counts of second-degree murder. He received 142 – 179 years in prison.

After its approval, Ambien quickly rose to dominance in the sleep aid market. Travelers swore by it to combat jet lag. And women, who suffer more insomnia than men, purchased it in droves. Sanofi, Ambien’s French manufacturer, made $2 billion in sales at its peak. In 2007 the generic version of Ambien was released, Zolpidem, and at less than $2 per pill, it still remains one of the most prescribed drugs in America, outselling popular painkillers like Percocet and prescription strength ibuprofen.

Not all prosecutors will consider the Ambien defense, and its position within established criminal rules is tenuous. It does not really fall under “voluntary intoxication,” in which someone is responsible for his own intoxication and any events that occur as a result of that intoxication.

Image via Corepics VOF / Shutterstock.

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Medical Marijuana – A Magic Bullet for Treating PTSD? http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/ http://brainblogger.com/2013/12/07/medical-marijuana-a-magic-bullet-for-treating-ptsd/#comments Sat, 07 Dec 2013 12:00:52 +0000 http://brainblogger.com/?p=15638 A new battle has been waged on Capitol Hill surrounding the much-debated legalization of medical marijuana. As research continues solidifying the positive effects of using cannabis to treat certain clinical symptoms, some research is focusing on the possible effects it may have on treating Post Traumatic Stress Disorder (PTSD).

Since the 1990s, organizations including the Multidisciplinary Association for Psychedelic Studies (MAPS) have attempted to further the development of research protocols surrounding the use of medical marijuana.

It was not until March 2011 that the National Cancer Institute acknowledged the viability of using marijuana in various treatment protocols. MAPS has continued its work to initiate further research and legislation requiring the National Institute on Drug Abuse and the Drug Enforcement Administration to loosen its reins and allow scientific organizations to grow their own cannabis for research purposes.

Viable research continues to evidence the positive impact medical marijuana has had on the lives of those suffering from cancer, glaucoma, multiple sclerosis, and other symptomatic disorders and diseases. It is also widely recognized that some individuals suffering from PTSD already use recreational drugs, including the illegal use of marijuana, to offset symptoms of the disorder. A 2012 case study focusing on a male patient with a variety of PTSD symptoms, severe in nature, revealed some symptoms were significantly reduced “by smoking cannabis resin.”

Further studies have focused on the molecular etiology of PTSD in reference to elevated brain cannabinoid CB1 receptors, along with endocannabinoid signaling systems. Research implies that the increased CB1 receptor-mediated anandamide signaling may play a role in some PTSD symptoms. As such, this research may provide evidence-based opportunities for drug therapies by utilizing a neurobiological model as presented in positron emission tomography studies.

The field of psychiatric medicine recognizes the distinct commonality of specific symptoms associated with PTSD, including severe flashbacks as well as uncontrollable panic attacks. How and why do memories of traumatic events affect the biological nature of the brain with such intensity? Evidence continues to support the theory that the endocannabinoid system holds primary influence over the regulation of memory and emotional behavior. Therefore it is reasoned that the evidence-based research focusing on the affects that THC and medical marijuana have had in other case studies may provide the same results with some symptoms exhibited in patients suffering from the PTSD.

Many social and political barriers continue to plague the future of not only the research of possible treatment options for medical marijuana, but also the legalization and use of its byproducts. It is difficult for society to erase the visual memories of soldiers smoking marijuana depicted through media sources throughout the Vietnam War. Vivid memories of young “hippie-garbed” individuals dancing in the rain while listening to rock-and-roll music and smoking “reefer” often wash over the eyes of many Americans who struggle with the concept of legalizing medical marijuana. Many politicians recognize the possible fall-out that may occur in supporting the legalization of medical marijuana, along with the difficulties involved in management of the sale and use of a perceived controlled substance.

There is no cut and dried solution to overcoming the possible negative implications of complete legalization of a product, such as marijuana, for medical purposes. Many government agencies are cautious of approving less restrictive regulations surrounding prescribed treatments using cannabis.

Yet, the number of individuals suffering from PTSD continues to grow. Many of these people maintain an active search for treatments that provide even the slightest bit of relief from often debilitating symptoms. The addition of military personnel suffering from PTSD is likely to lend greater support for continued research and legalization of medical marijuana as a viable treatment option.

References

Akirav I. (2013). Targeting the endocannaabinoid system to treat haunting traumatic memories. Frontiers in Behavioral Neuroscience 7: 124. PMCID: PMC3776936

Neumeister A, Normandin MD, Pietrzak RH, Piomelli D, Zheng MQ, Gujarro-Anton A, Potenza MN, Bailey CR, Lin SF, Najafzadeh S, Ropchan J, Henry S, Corsi-Travali S, Carson RE, & Huang Y (2013). Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Molecular psychiatry, 18 (9), 1034-40. PMID: 23670490

Passie T, Emrich HM, Karst M, Brandt SD, & Halpern JH (2012). Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug testing and analysis, 4 (7-8), 649-59 PMID: 22736575

Image via Yarygin / Shutterstock.

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Are Psychoactive Drugs a Thing of the Past? http://brainblogger.com/2013/11/01/are-psychoactive-drugs-a-thing-of-the-past/ http://brainblogger.com/2013/11/01/are-psychoactive-drugs-a-thing-of-the-past/#comments Fri, 01 Nov 2013 11:00:46 +0000 http://brainblogger.com/?p=15547 Before I actually get started on this article, I would like to immediately answer the question I posed in the title: no. Psychoactive drugs are alive and well. But they might not be for long.

In a recent article titled “Changing brains: why neuroscience is ending the Prozac era”, The Observer reports that large pharmaceutical companies have, for the most part, significantly slowed research on new drugs.

We already have drugs meant to treat pretty much any problem, and it has been a long time since the era of discovering revolutionary new prescription medications on a regular basis. Now, the occasional new drug has the same effects as a previous one, but it provides fewer side effects. Better, yes, but hardly exciting. And because of this, Big Pharma has largely ceased funneling major research dollars into new psychoactive drugs.

But that does not mean they are slowing their research. Pharmaceutical companies are still investing billions of dollars every year in new technologies and methods for treating various diseases.

So what are they working on now? One of the major up-and-coming areas is optogenetics, a term that you’ll likely be hearing about quite a bit over the next several years. Optogenetics is a fascinating neuroscientific field that may soon allow scientists to stimulate specific networks of neurons — a far more fine-grained approach than altering neurotransmitters, as many current psychoactive drugs do.

Optogenetics is based on a very interesting technological method. First, a virus containing the genetic details for light-sensitive proteins is injected into the brain. This virus “infects” a specific population of neurons, making them reactive to a specific wavelength of light (generally in the blue range). Next, tiny fiber optic cables are implanted in the brain, also targeting specific neurons. When a pulse of light is sent through the cable, the neuron is activated or inhibited.

It sounds like science fiction, but it’s not. In fact, they’ve actually been using a similar strategy to treat Parkinson’s disease for a while now, though they use electrodes instead of fiber-optics. Obviously, the electrodes offer significantly less fine control. And over the next decade or so, you can expect to see billions upon billions of dollars spent on research in this area. They have successfully used this technology in mice, but as of yet, there have been no human trials (at least that I am aware of).

But this kind of research brings with it very important philosophical considerations. Many cognitive scientists — including neuroscientists — have an essentially mechanistic view of the brain-mind-body interface; desires, preferences, and actions are determined by chemical and electrical reactions in the brain, all coming together to make us who we are. There is little room for the idea of a soul or, sometimes, even free will in this kind of view.

If this is the case, what happens to us when we fundamentally alter the brain and use that to affect changes in behavior? The change in behavior could be something as significant and positive as inhibiting suicidal behavior or encouraging compassion. What does this mean for us as people? Does this change who we are? If so, should we allow Big Pharma, an industry known for manipulating medicine and academic research to its own purposes, to dictate how this technology works and is applied?

There are a lot of questions surrounding optogenetics, and these are just a few. Share your thoughts in the comments below, and let us know what you think about optogenetics and its potential future uses.

References

Bell, V. (2013). Changing brains: why neuroscience is ending the Prozac era. The Observer, Sunday 22 September.

Image via Bluerain / Shutterstock.

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Amyvid Alzheimer´s Testing – To Be Or Not To Be? http://brainblogger.com/2013/10/14/amyvid-alzheimers-testing-to-be-or-not-to-be/ http://brainblogger.com/2013/10/14/amyvid-alzheimers-testing-to-be-or-not-to-be/#comments Mon, 14 Oct 2013 11:00:06 +0000 http://brainblogger.com/?p=15428 The FDA approved Amyvid for Alzheimer´s testing in April 2012, yet Medicare and Medicaid denied coverage for it last July. The new brain imaging drug helps detect beta-amyloid neuritic plaques in the brain, which are associated with Alzheimer´s disease. In the past, in order to detect these plaques, a biopsy had to be performed. But the test remains controversial — will it be taken up?

There are about five million Americans suffering from Alzheimer´s disease today, and analysts predict that this number could double by 2050. This constitutes a huge market for pharmaceutical companies trying to develop effective drugs against what remains an incurable condition. Amyvid developer Lilly & Co is one of them, and it is currently working on an experimental drug called Solanezumab. While Amyvid testing is now available in numerous locations around the US, coverage would completely change the landscape of Alzheimer´s diagnosis in the country by clearly identifying the markets for solanezumab and other similar drugs. 

Amyvid is a radioactive agent that is injected into patients prior to performing a 30-minute PET scan. The drug directly highlights amyloid neuritic plaques present in the brain. One of the claims Medicare made against Amyvid testing is that it does not directly establish an Alzheimer´s diagnosis, because there are other conditions associated with cognitive impairment that can cause a high density of neuritic plaques in the brain. However, the new brain imaging technique can reliably rule out Alzheimer´s when the plaques are not present. Studies have shown that 20% to 50% of Alzheimer´s patients in America have been misdiagnosed with the disease, and there seems to be a consensus as to the enormous potential of Amyvid testing to reduce this type of misdiagnosis.

A 2011 survey by the Harvard School of Public Health revealed that 85% of respondents would be willing to be tested for Alzheimer´s if they ever exhibited signs of cognitive impairment, such as memory loss. However, as the test is currently not covered by insurance or Medicare, and its cost of $3000 is rather steep, testing is currently limited to those who can afford it.

As Lilly & Co awaits a final decision about coverage in October 2013, Alzheimer´s patients and researchers associations argue that if the new imaging scan were to be covered by health insurance, the data collected from Alzheimer´s patients worldwide would greatly help researchers develop new treatments for this prevalent disease. Medicare representatives, on the other hand, claim that testing can be of no help so long as Alzheimer´s disease remains incurable.

While results for Solanezumab and other Alzheimer´s treatments in development are still far from commercialization, a definite Alzheimer´s diagnosis would be required in order to treat patients with these drugs. Although there is some truth to Medicare´s argument about neuritic plaques proliferating in the brain in patients with conditions other than Alzheimer´s, the fact is that Amyvid has revolutionized Alzheimer´s diagnosis. Amyvid testing may not be perfect, but it is surely a huge step forward in Alzheimer´s research, and it has great potential to aid the development of new treatments for this prevalent disease.

References

Blendon, R. J. et al. Key Findings from a Five-Country Survey of Public Attitudes about Alzheimer’s Disease. Poster presented at AAIC, July 2011.

Gandhi, H.; Hewing, D.; Botkin, C.; Hubble, W.; Turner, J.; Osman, M. (June 2013). Amyvid: A Review and assessment of clinical implementation. Journal of Nuclear Medicine and Molecular Imaging Meeting.

US Food and Drug Administration. Press Release (April 2012): FDA Approves Imaging Drug Amyvid.

American Academy of Neurology (2011, February 24). Alzheimer’s disease may be easily misdiagnosed. ScienceDaily.

World Health Organization fact sheet (February 2007). The top ten causes of death.

Alzheimer’s Association (2011). Alzheimer’s Disease Facts and Figures

Image via SFAM Photo / Shutterstock.

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The Overlooked Role of Universities in the Drug Discovery Process http://brainblogger.com/2013/06/04/the-overlooked-role-of-universities-in-the-drug-discovery-process/ http://brainblogger.com/2013/06/04/the-overlooked-role-of-universities-in-the-drug-discovery-process/#comments Tue, 04 Jun 2013 11:00:35 +0000 http://brainblogger.com/?p=14730 Drug discovery is the process by which novel therapeutic candidates are discovered and ultimately developed into human-grade medications. These candidates may include compounds ranging from modified or unmodified natural products or extracts and small molecules to biologics. Forbes reports that the average cost of drug development for a major pharmaceutical company is between $4 billion and $11 billion, which is a great deal higher than the more commonly reported $1 billion, as it accounts for failure rates. And in fact, failure rates are an important part of the drug discovery process.

Estimates show there is a 1 in 30 chance for the identification of an initial drug target to result in a product launch. Furthermore, reports indicate that it can take more than 12 years from the initial molecular target discovery to progress through preclinical studies and ultimately to US Food and Drug Administration (FDA) regulated human clinical trials. Costs accrue throughout this lengthy process for various items including personnel, research materials, collaborations, patent filings, clinical trials, and regulatory applications.

Many people tend to associate the development of drugs with the large pharmaceutical companies that sell them including Johnson & Johnson, Pfizer, and Merck & Co., to name a few. However, in most cases the critical initial discovery role of the smaller organization is overlooked.

A recent agreement between Eisai, one of the largest pharmaceutical companies based on revenue, and Johns Hopkins University Brain Science Institute (JHUBSi) represents the current push in university-private sector collaboration for drug discovery. In this arrangement, JHUBSi is tasked with taking the lead in identifying novel compounds to potentially treat neurological disorders and Eisai will have the option to further develop and commercialize these leads through a licensing agreement. The university stands to benefit financially from the potential receipt of up front payments, royalties, and negotiated milestone payments once a licensing agreement is reached.

Interestingly, of the 252 new drugs approved by the FDA from 1998 to 2007, approximately 24% originated from University or biotechnology company research and were subsequently transferred to a pharmaceutical or biotechnology company to further the research and develop a product that could be marketed. These data verify the fundamental role for university research and suggest that technology transfer is an essential component to the development of therapeutics.

In fact, university research has resulted, in part, in the development of many well-known therapeutics including insulin as a treatment for diabetes, various tuberculosis antibiotics, Allegra, and multiple chemotherapeutic agents such as Cisplatin. University research has contributed to the development of other areas of technology transfer and product commercialization, including in the development of various vaccines, medical devices such as the ultrasound and the pacemaker, and everyday items such as the seat belt and Google.

While the role of large pharmaceutical companies is integral in the development of novel drugs, it is important to also note that universities and biotechnology companies play an important, and often overlooked role as well. Industry-academia collaborations may represent the future of drug development and it is predicted that in years to come, we will see more than 24% of novel drugs originating from technologies developed by universities and biotechnology companies.

References

Bains, W., Drug Discovery World, (Fall 2004). Failure rates in drug discovery and development: will we ever get any better?

Herper, M., Forbes, (October 2012). The Truly Staggering Cost Of Inventing New Drugs.

Kneller, R. (2010). The importance of new companies for drug discovery: origins of a decade of new drugs Nature Reviews Drug Discovery, 9 (11), 867-882 DOI: 10.1038/nrd3251

Image via Alex011973 / Shutterstock.

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Promoting Remyelination in Multiple Sclerosis – an Interview on rHIgM22 http://brainblogger.com/2013/06/02/promoting-remyelination-in-multiple-sclerosis-an-interview-on-rhigm22/ http://brainblogger.com/2013/06/02/promoting-remyelination-in-multiple-sclerosis-an-interview-on-rhigm22/#comments Sun, 02 Jun 2013 11:00:39 +0000 http://brainblogger.com/?p=14968 The Mayo Clinic and Acorda recently enrolled the first patient in their phase 1 clinical trial of a remyelinating antibody that may potentially reverse the damage caused by multiple sclerosis. I recently interviewed Anthony O. Caggiano, MD, PhD, Vice President of Research & Development at Acorda since February 2009. Since joining Acorda in 2001, he has served in various roles in preclinical science and research and development, directing basic research and product development efforts, coordinating external research programs with academic and commercial partners, and collaborating in business development activities.

SL: What is the current state of knowledge on the pathogenesis of multiple sclerosis?

AC: In multiple sclerosis (MS), a person’s own immune system destroys myelin, a substance that insulates nerves and facilitates conduction of nerve impulses that control neurological function such as movement and vision. Without myelin, the neurons in the brain, spinal cord or central nervous system communicate less effectively.

Progressive damage to myelin causes functional impairment in people with MS. Currently there are no approved therapies that stimulate the repair or regrowth of myelin once it has been damaged. Acorda is now studying an antibody called rHIgM22 which has been shown to potentially stimulate remyelination and improve the function of neurons.

SL: How do our current lines of treatment for MS affect the disease course?

AC: There are two main categories of MS treatments. The first involves the use of disease-modifying agents (interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab and fingolimod), which have been found to help with relapse management, decrease MRI activity and potentially delay disability. The second category is treatments that target specific symptoms of MS, such as AMPYRA (dalfampridine), which is indicated to improve walking in people with MS.

Disease-modifying agents are an important part of managing MS, and evidence suggests that they can be combined with other treatments to target different aspects of immune response or therapeutic targets such as inflammation or neuroprotection.

SL: How was rHIgM22 identified and what does it target?

AC: rHIgM22 was identified by a team at the Mayo Clinic led by Moses Rodriguez, MD, a neurologist specializing in MS. It is a monoclonal antibody that interested Dr. Rodriguez because of its ability to enhance the repair of the central nervous system (CNS). The cells that make myelin, called oligodendrocytes, can initially repair myelin, but as MS progresses, there is little spontaneous repair. Dr. Rodriguez’s team identified antibodies in mice that promote remyelination and then identified similar antibodies in humans. rHIgM22 is the lead of these human derived antibodies and has been shown to bind CNS myelin, stimulate oligodendrocytes and promote remyelination in animal models.

rHIgM22 is currently being studied in a double-blind, randomized, single ascending dose Phase 1 clinical trial in people with MS. This study will measure the safety and tolerability of rHIgM22 as well as any changes in the MRI results of treated patients. Evaluations of changes in MS symptoms, such as walking ability, will also be conducted.

SL: What is in on the brinks of translating from the benchside to the bedside in MS?

AC: Many researchers are continuing to develop disease modifying therapies and symptom management medications in MS, but research related to remyelination is positioned as a major focus in research in the years ahead. Such therapies have the potential to represent a novel and significant advance in MS care.

References

Rodriguez M, Warrington AE, & Pease LR (2009). Invited article: human natural autoantibodies in the treatment of neurologic disease. Neurology, 72 (14), 1269-76 PMID: 19349608

Watzlawik J, Holicky E, Edberg DD, Marks DL, Warrington AE, Wright BR, Pagano RE, & Rodriguez M (2010). Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytes. Glia, 58 (15), 1782-93 PMID: 20645409

Watzlawik JO, Warrington AE, & Rodriguez M (2013). PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PloS one, 8 (2) PMID: 23383310

Image via martan / Shutterstock.

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Treating Acute Ischemic Stroke – The Race Is On http://brainblogger.com/2013/06/01/treating-acute-ischemic-stroke-the-race-is-on/ http://brainblogger.com/2013/06/01/treating-acute-ischemic-stroke-the-race-is-on/#comments Sat, 01 Jun 2013 11:00:27 +0000 http://brainblogger.com/?p=14338 As the fourth leading cause of death in the U.S. and a leading cause of permanent disability, stroke has an incredible impact at both the individual and economic level. According to the CDC, an American dies every 4 minutes as the result of an acute stroke. With 87% of these strokes being ischemic in nature, rapid assessment and diagnosis of patients with stroke symptoms is required in order to ensure that eligible patients receive fibrinolytic therapy within the recommended time frame (around 3 hours). Research has shown that although healthcare providers in the inpatient setting are greatly reducing delays to treatment, there is still much work to be done in the pre-hospital setting to ensure that valuable time is not lost.

Researchers in Finland demonstrated that over a two year period hospitals were able to reduce average delays of treatment initiation by approximately 50%. Similar restructuring has occurred within the U.S. as hospitals started to be designated as ‘stroke centers’ by the Joint Commission — the nation’s leading hospital accrediting body. To achieve stroke center accreditation, hospitals have to meet a set of criteria demonstrating they effectively manage acute stroke based on current medical research. These criteria include having an on call neurologist, the availability of CT imaging, and designated critical care units for stroke patients. These criterions have ensured that more patients are able to receive life-saving thrombolytic therapy. Despite these remarkable efforts, however, there is much yet to be done to improve outcomes for patients with acute stroke.

Kwan and his team of researchers analyzed 54 studies that sought to identify barriers to patients receiving thrombolytic therapy. They found that only 37% of patients in the UK arrived in the hospital within three hours of symptom onset. This would seem to suggest that substantial delays occur in the pre-hospital setting. Such delays were the number one reason cited why patients did not receive rt-PA, with 22-94% of patients being rendered ineligible due to lost time. The number one pre-hospital delay cited in the literature was patient or family delay in requesting medical help due to a lack of knowledge on signs of stroke. The logical next step would seem to be the development of advertisement campaigns with the goal of educating the public on the signs and symptoms of stroke.

Unfortunately, such attempts at education have thus far not been remarkably fruitful. Lecouturier found that education programs directed towards a public audience have been shown to increase the awareness of the signs and symptoms of a stroke, but seem to have had little to no impact on behaviors. One study showed that even after education, contacting emergency medical services (EMS) did not occur until almost 2 hours after symptom onset. This extreme delay makes it unlikely that patients will arrive to an inpatient setting within a 3 hour window to begin thrombolytic therapy.

Earlier research by Moser suggests that perhaps educational opportunities are misdirected. Specific educational programs directed at persons of lower socioeconomic status or those of black or Hispanic descent have not been greatly documented while these groups have among the highest delays in seeking treatment for stroke. Likewise, patients with a prior diagnosis of hypertension are at a significant risk for stroke and may benefit from more directed education.

Additionally, Moser’s findings suggest that the best place to improve education may be within the professional realm. To reduce pre-hospital delay to treatment, the researchers suggest that EMS dispatch teams should rearrange protocols to give a higher priority in dispatching units to suspected stroke victims; some research has suggested that more rural areas do not attribute the same triage priority to stroke as they do to acute coronary syndrome.

Another group that may benefit from further education is paramedics. A nationwide survey showed that paramedics were competent on knowledge of stroke symptoms but were unaware of the treatment window for fibrinolysis. Education and protocol reform may help to ensure more rapid diagnosis and transport of stroke victims by EMS.

Medical literature has made it abundantly clear that the number one factor in reducing morbidity and mortality for patients with acute ischemic stroke is final diagnosis and disposition to the stroke unit in under three hours. This rapid sequence ensures that those patients eligible for rt-PA can receive it within the therapeutic time frame. Much research and interventions must still take place if this is to be achieved for the greatest possible number of patients. Population specific education, restructuring of EMS protocols, and continuing education of paramedics may be the first major steps towards successful mitigation of the devastating effects of stroke.

References

Kwan J, Hand P, & Sandercock P (2004). A systematic review of barriers to delivery of thrombolysis for acute stroke. Age and ageing, 33 (2), 116-21 PMID: 14960425

Lecouturier J, Rodgers H, Murtagh MJ, White M, Ford GA, & Thomson RG (2010). Systematic review of mass media interventions designed to improve public recognition of stroke symptoms, emergency response and early treatment. BMC public health, 10 PMID: 21182777

Moser DK, Kimble LP, Alberts MJ, Alonzo A, Croft JB, Dracup K, Evenson KR, Go AS, Hand MM, Kothari RU, Mensah GA, Morris DL, Pancioli AM, Riegel B, & Zerwic JJ (2006). Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on cardiovascular nursing and stroke council. Circulation, 114 (2), 168-82 PMID: 16801458

Puolakka T, Väyrynen T, Häppölä O, Soinne L, Kuisma M, & Lindsberg PJ (2010). Sequential analysis of pretreatment delays in stroke thrombolysis. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 17 (9), 965-9 PMID: 20836777

Image via Rihardzz / Shutterstock.

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Psychopharmacological Drug Development in A Depression? http://brainblogger.com/2013/05/14/psychopharmacological-drug-development-in-a-depression/ http://brainblogger.com/2013/05/14/psychopharmacological-drug-development-in-a-depression/#comments Tue, 14 May 2013 11:00:47 +0000 http://brainblogger.com/?p=14601 “If you are a mouse and suffer from depression, we can cure you!”.

You may have heard similar statements for other diseases, which is a general reflection on the current state of drug development. After spending billions of dollars in pharmaceutical drug development only about 30 new drugs reached the market last year — a number that is higher than in previous years, but still. It’s not good news for patients, especially those suffering from mental illness, for whom the outlook on new drugs is even bleaker. Why the dry pipeline?

Mental diseases are difficult to treat. Drug development in particular is hampered by the following key obstacles:

Unknown causes

Firstly, the cause of most mental diseases at the molecular level is often unknown, making it difficult to tackle a target with a pill. In oncology for example, molecular targets have been identified and in certain cases, a single point mutation in a gene has been identified as the cause for the disease. Subsequently, specific drugs have been developed against that target and patients are screened for specific mutations to determine whether they are suitable candidates for that treatment or not.

Unfortunately this is not the case for many mental disorders. The first generation of approved antidepressants was found through serendipity by observant physicians. After that, a few more classes of antidepressants emerged, mostly reducing the undesirable side effects associated with first generation drugs. Nevertheless, the exact mode of action of most antidepressants in the human brain remains unclear.

Variable drug response

Secondly, as with any drug, not all patients respond equally to a particular treatment. In a 9-year study investigating the quality of care in patients with depression the percentage of non-responders was around 25%. More pessimistic estimates put the number as high as 50%. It is not uncommon for patients with depression to try several antidepressants before they find one that works or before they give up on it.

Within the last five years, a debate on the efficacy of antidepressants has emerged. One study accused the publishing bias towards positive trial data of skewing our views on the therapeutic effectiveness of antidepressants. The researchers looked back at 74 studies with 12,564 registered patients that were reported to the FDA. 38 of these studies were considered to be positive by the FDA. All of the positive studies were published, except one. In contrast, only a third of the studies, which were considered negative or ambiguous, were published. Even then negative data were misrepresented, according to the investigators.

Similar conclusions were drawn in a recent study on antipsychotic drugs. This is not to say that antidepressants or antipsychotic drugs don’t work. We may have just overestimated their effectiveness. The debate highlights the difficulty in finding effective pills with our current medical knowledge and empirical approach.

The difficulty of using animal models

Thirdly, in the pre-clinical stage of drug development, animal models are used to screen for toxicity and efficacy. The crux here is in the word “model”. No animal model is perfect. There is an inherent risk for failure when the drugs are finally administered to humans. These failures are dramatic for patients, and costly for the industry. Recent failures of late-stage drugs developed against schizophrenia, pain and Alzheimer’s disease are testimony to that statement.

Then what’s the solution?

Changes to the drug development paradigm seem to be required. A better understanding of pathological mechanisms and therapeutic effects is needed. Most notably, “personalized approaches that use biomarkers, including neurophysiological, neuroimaging, genetic, and neuropsychological techniques, are required to guide treatment”. Broadening the scope of clinical trials is already commonplace for drugs in other disease areas. Although costly, such an extension is feasible and of merit.

Also, the Brain Activity Map program seems to have traction. The project is a coordinated effort of government agencies, universities, and the private sector to create a comprehensive understanding of the brain’s function. Similar to the Human Genome Project, the approach would start with the investigation of simple organisms leading up to the human species. Obviously, the challenges are enormous, but one of the outcomes of that project could be a better understanding of the normal brain function leading to better ways of treat mental disease.

Promising technologies such as induced pluripotent stem cells, in vitro neuronal circuits, and connectomics will be discussed in an upcoming workshop at Institute of Medicine of the National Academy of Sciences. The title of this workshop is “Accelerating Therapeutic Development for Nervous System Disorders towards First-in-Human Trials”. Not only scientific tools but also regulatory and ethical issues are key topics of the meeting agenda. The problems have been recognized. The search for solutions is on. There is light at the end of the tunnel.

References

Alivisatos AP, Chun M, Church GM, Deisseroth K, Donoghue JP, Greenspan RJ, McEuen PL, Roukes ML, Sejnowski TJ, Weiss PS, & Yuste R (2013). The Brain Activity Map. Science (New York, N.Y.) PMID: 23470729

Fullerton CA, Busch AB, Normand SL, McGuire TG, & Epstein AM (2011). Ten-year trends in quality of care and spending for depression: 1996 through 2005. Archives of general psychiatry, 68 (12), 1218-26 PMID: 22147841

Mathew, S., & Charney, D. (2009). Publication Bias and the Efficacy of Antidepressants American Journal of Psychiatry, 166 (2), 140-145 DOI: 10.1176/appi.ajp.2008.08071102

Turner EH, Knoepflmacher D, & Shapley L (2012). Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS medicine, 9 (3) PMID: 22448149

Turner EH, Matthews AM, Linardatos E, Tell RA, & Rosenthal R (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. The New England journal of medicine, 358 (3), 252-60 PMID: 18199864

Image via avarand / Shutterstock.

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On the Path to Preventing Alzheimer’s Disease http://brainblogger.com/2013/03/23/on-the-path-to-preventing-alzheimers-disease/ http://brainblogger.com/2013/03/23/on-the-path-to-preventing-alzheimers-disease/#comments Sat, 23 Mar 2013 11:00:35 +0000 http://brainblogger.com/?p=14256 Nearly 30 million people worldwide are affected by the Alzheimer’s disease (AD) and the most recent estimates indicate that this number will quadruple within the next 40 years. The concern increases as AD is the leading cause of dementia, and, so far, there is no effective treatment to slow the progression or delay the onset of this malady.

It is known that AD is a disease of protein aggregation mainly involving accumulation of beta-amyloid (Abeta) in the brain, a peptide of 36-43 amino acids, mostly in the form of tau fibrils and amyloid plaques.

Currently, 10 genes have been identified as influencers of the AD’s risk. The autosomal dominant mutations in the precursor protein (APP) and presenilin (PSEN) genes encoding amyloid precursor protein and the presenilin proteins are accepted as the causes of the hereditary forms of AD.

Most of these mutations increase total Abeta or Abeta42 production, leading to an increased amyloid plaque formation — a pathological hallmark of AD. Thus, Abeta lowering has become a vital therapeutic goal, with various paths within antibodies against Abeta (anti-Abeta) being tested. Over the past few years, the research has been mostly developed after the detection of disease, pursuing a means of lowering the production of the Abeta by inhibiting the enzymes responsible for the generation of this peptide, preventing the formation of Abeta aggregates, and increasing the rate of Abeta clearance from the brain. Presently, several different anti-Abeta therapies are in clinical trials worldwide. Although some modest reductions in plaque burden have been achieved, no obvious clinical benefit or arrest in the progression of cognitive decline was further confirmed.

Given this lack of success, the Alzheimer’s research community has moved toward a consensus that diagnosing and treating the disease before overt symptoms may be more advantageous to slow the disease’s pathogenic process. Among this novel approach, has been particularly suggested that pre-symptomatic individuals with deterministic mutations in APP, PSEN1, or PSEN2 could undergo treatment with an anti-Abeta agent before the expected age of onset of frank symptoms. Individuals with brain amyloid deposits (detected by positron emission tomography) exceeding normal thresholds, as well as low cerebrospinal fluid Abeta 42 levels, may respond to an anti-Abeta treatment.

The Dominantly Inherited Alzheimer Network (DIAN) investigators showed that the changes in cerebrospinal fluid levels of Abeta42 that accompany Abeta deposition are possible to be detected nearly 25 years before the symptom’s onset. This suggests that, in persons with mutations for dominantly inherited AD, the primary prevention with anti-Abeta agents might need to begin, at least, 25 years before the earliest signs.

Following this lead, a prevention trial with an anti-Abeta in around 300 presymptomatic individuals with presenilin mutations has been approved to be carried out by an academic consortium sponsored in part by the United States National Institutes of Health (NIH) and a biotechnology company. Still in the domain of the autosomal dominant AD, another secondary prevention trial has been proposed to the NIH by the Dominantly Inherited Alzheimer Network, the Alzheimer’s Association and some pharmaceutical companies.

Nevertheless, beyond these prevention trials in presymptomatic participants with rare, dominantly inherited AD, there is an intention to initiate similar studies in presymptomatic persons with common, late-onset (so-called sporadic) AD. Hereupon, another secondary prevention trial of an anti-Abeta in sporadic AD subjects (the A4 trial) will be carried out by a consortium led by the Alzheimer’s Disease Cooperative Study group funded by NIH. They recently announced the selection of Eli Lilly’s monoclonal antibody solanezumab as the first therapeutic drug to be evaluated.

Will this novel approach help overcoming this terrible disease? We shall see.

References

Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, & Xiong C (2011). Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimer’s research & therapy, 3 (1) PMID: 21211070

Gandy S (2012). Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. The New England journal of medicine, 367 (9), 864-6 PMID: 22931321

Golde TE, Schneider LS, & Koo EH (2011). Anti-a? therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron, 69 (2), 203-13 PMID: 21262461

Holtzman DM, Morris JC, & Goate AM (2011). Alzheimer’s disease: the challenge of the second century. Science translational medicine, 3 (77) PMID: 21471435

Holtzman DM, Goate A, Kelly J, & Sperling R (2011). Mapping the road forward in Alzheimer’s disease. Science translational medicine, 3 (114) PMID: 22190237

NIH Fogarty International Center. First-ever Alzheimer’s prevention trial to take place in Colombia. 2012.

Selkoe DJ (2012). Preventing Alzheimer’s disease. Science (New York, N.Y.), 337 (6101), 1488-92 PMID: 22997326

Image via Sebastian Kaulitzki / Shutterstock.

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Nootropics Reduce the Severity of Brain Trauma http://brainblogger.com/2013/01/29/nootropics-reduce-the-severity-of-brain-trauma/ http://brainblogger.com/2013/01/29/nootropics-reduce-the-severity-of-brain-trauma/#comments Tue, 29 Jan 2013 12:00:17 +0000 http://brainblogger.com/?p=14092 Recovery from brain trauma like injury or a stroke is a complex process and one that is not yet under precise human control. More often than not, the process of resumption of blood flow to injured parts of the brain also creates additional damage. In addition to physical damage, exposure to extreme conditions like sub-zero temperatures as well as extremely hot conditions can also result in damage to neurons.

Pharmacological options to help recovery from stroke as well as physical brain injury are limited. Patients are often left paralyzed after a stroke. One approach, to get around the fact that only a small number of post hoc curative options are available in this area of medicine, has been to pre-condition the physiological system to withstand trauma. Several plant-derived substances as well as synthetic ones have been tried out to help the brain adjust to adverse environmental conditions (very cold and very hot) as well as to physiological insults like deprivation of oxygen. These “adaptogens” or molecules that help to adapt have been known as nootropic molecules or simply nootropics. Some nootropics like an extract from Bacopa monnieri also help to enhance memory and cognitive functions even in the absence of brain trauma.

The list of known nootropics is growing and the latest molecules to join the club are Cerebrolysin and GYKI-52466. Cerebrolysin is a mixture of neuropeptides that promotes growth of neurons, thereby diminishing the impact of environmental insults. GYKI-52466 is an anti-convulsant drug.

Exposure to very hot conditions has been shown to induce neurological and behavioral changes in experimental animal models. Rats exposed to whole body hyperthermia (4 hours at ambient temperature of 38C displayed behavioral changes and impaired motor functions. Neurotransmitters like glutamate and aspartate were elevated in these rats whereas the levels of glycine and GABA had reduced under these conditions. Anatomical studies also revealed damage to neurons as well as glial cells and a breakdown of the blood-brain barrier. Usually, the blood-brain barrier in cranial blood vessels is stringently permeable to very few substances. A breakdown in the blood-brain barrier signifies greater chances of permeation of blood borne toxins and viruses into neural tissue.

These effects of exposure of the whole body to extremely hot conditions can be reversed by administration of Cerebrolysin, if it is given within one hour of exposure. In experiments carried out by Drs. Sharma, Sharma, Mossler and Muresanu, damage to brain cells could be prevented if the animals were given Cerebrolysin 30 minutes prior to exposure to high heat or within one hour post exposure. Delayed administration of Cerebrolysin did not help recovery from brain damage resulting from these conditions.

These findings are important in light of the fact that exposure of people to such temperatures is possible. Consider the daytime temperatures in places like hot deserts where temperatures of 49 degrees Celsius (Thar Desert, India), 40C (Great Victoria Desert, Australia), 58C (Sahara Desert, Libya), 50C (Gobi Desert, Mongolia) have been recorded in summer. The Afar depression in Ethiopia, which incidentally is inhabited by humans, has daytime temperatures of 48C in summer with the highest recorded temperature being 64.4C. In steel mills, in some of the hottest sections, workers may be exposed to ambient temperature of 56C.

Nootropics like Cerebrolysin may help to recover from the damage caused by whole body hyperthermia in these situations, particularly in the manufacturing industry. People from endemic cultures of hot desert regions have presumably adapted to living under these conditions and the effects of administration of nootropics to such people is probably a whole new area of investigation. However, if occasional exposure is indicated for people who otherwise would remain in a comfortable ambiance, then treatment with cerebrolysin would perhaps help to reduce the damage caused by whole body hyperthermia.

GYKI-52466 is an antagonist of the glutamate receptor which is primarily used to treat convulsions and acts as a skeletal muscle relaxant. In a recent paper, Drs. Nayak and Kerr have described experiments conducted on rats where administration of low doses of GYKI-52466 helped to reduce the extent of brain damage resulting from an induced stroke. Loss of brain tissue was lesser in animals pre-treated with GYKI-52466 than that seen in control animals which were not given the drug. Behavioral traits were also less affected in rats treated with GYKI-52466 as compared to animals not exposed to the drug.

Research into both these nootropics is in progress and accumulation of more data is certainly warranted. However, there seems to be evidence that favors prophylactic prescription of such drugs to people who are at greater risk of suffering from hyperthermia or stroke.

References

Masliah E, & Díez-Tejedor E (2012). The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs of today (Barcelona, Spain : 1998), 48 Suppl A, 3-24 PMID: 22514792

Nayak PK, & Kerr DS (2012). Low-dose GYKI-52466: Prophylactic preconditioning confers long-term neuroprotection and functional recovery following hypoxic-ischaemic brain injury. Neuroscience PMID: 23246617

Sharma HS, Sharma A, Mössler H, & Muresanu DF (2012). Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. International review of neurobiology, 102, 249-76 PMID: 22748833

Image via VladisChern / Shutterstock.

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Locked-In – Lesson for Stroke Awareness http://brainblogger.com/2012/11/07/locked-in-lesson-for-stroke-awareness/ http://brainblogger.com/2012/11/07/locked-in-lesson-for-stroke-awareness/#comments Wed, 07 Nov 2012 12:00:51 +0000 http://brainblogger.com/?p=13616 After he suffered a stroke in 2005, Tony Nicklinson developed locked-in syndrome, a rare condition that left the middle-aged Brit fully paralyzed from the neck down. He lived on, mentally alert but wholly incapable of taking care of himself. He could not walk, feed himself or brush his own teeth. Devastated when a British court refused to allow him to commit assisted suicide, Nicklinson stopped eating or accepting fluids. He developed pneumonia, refused antibiotics, and died this past August 22, 2012.

Although news bulletins focused on his legal efforts to be permitted to commit assisted suicide, Nicklinson’s tragic disability — seven years of what his wife called a “living nightmare” — also bears upon stroke awareness and the availability of the emergency treatment that too few people know about or receive — the clot-busting drug, tissue plasminogen activator (tPA). Locked-in syndrome has something to say to everyone at risk for stroke. So does tPA.

In 2005, Stephan Mayer MD, together with colleagues at the Columbia University College of Physicians and Surgeons, reported on a unique case of heroic treatment to prevent locked-in syndrome in a stroke victim.

tPA and a Case of Locked-In Syndrome

Mayer’s patient, the pastor of a well-known church in Manhattan, suffered from a “stuttering course” of brainstem ischemia that lasted days. He first went to the emergency room some 10 hours after he began to experience facial numbness and right-side weakness. A history of neck pain suggested a vertebral dissection, or tear in the lining of the main artery that supplies blood to the brain. Transferred to the neurointensive care unit (Neuro-ICU), his symptoms were varied and ominous. First the left arm would become weak, afterwards the right; then one side of his face would become paralyzed. To insure he could breathe, he had to be intubated.

“We realized he was in the early stages of an evolving basilar artery syndrome,” recalls Mayer, “the final result of which, in the worst case, you infarct your whole pons and become locked-in.” Patients who end up in a complete locked-in state remain conscious but are completely paralyzed save for the vertical gaze. The condition is widely recognized as a fate worse than death.

Over two days Mayer presided over the patient’s disrupted “low flow state” in the occluded basilar artery of his brainstem. He administered heparin, an anticoagulant, and artificially raised his blood pressure but neither measure had any appreciable effect. An angiogram showed blood seeping into the basilar artery and small fragments of clotted blood. Occlusion of both vertebral arteries shut down the possibility of a mechanical solution such as angioplasty.

Suddenly, on the second day in the ICU, the patient became totally quadriplegic. Efforts to reverse it failed. Mayer went to the patient’s wife.

“I said, ‘We’re losing him. He’s going to develop this locked-in syndrome. We’ve got to try something.” He added: “The one thing I can think of doing is giving tPA.”

Were circumstances less than extraordinary, that meant breaking all the rules. “Forget the three hour [time window for giving tPA]; this ischemic process had been going on for two days.” Mayer was purposely keeping blood pressure high, at around 220 systolic, another contraindication. So was the anticoagulant he administered. Finally, a diagnosis of arterial dissection was not an approved use for tPA, which raised genuine concern for catastrophic hemorrhage.

“Look,” Mayer told the patient’s wife. “It’s high risk. But I don’t know what else to do. It’s a total roll of the dice and probably won’t work. But otherwise you’re going to just stand around and watch this guy become locked-in.”

With her approval, he administered tPA.

“I’ll be damned,” Mayer recalls. “About an hour later, he started to improve. He started to move both sides.” Sensation and movement fully returned. Within days he would walk out of the hospital.

“From a biological point of view, he was thrombosing [developing blood clots],” recalls Mayer. “By giving the tPA, it was just enough to open everything up.”

Mayer and his colleagues went on to write up the case, published in Neurocritical Care. They hoped to illustrate and underscore that, “Sometimes, when you’re facing certain doom, you can roll the dice, break the rules, as long as you have eyes wide open about the risks and benefits.”

The contrast in outcomes between Mayer’s case and that of Tony Nicklinson also points to the importance of stroke awareness and knowing about the use of tPA to treat stroke, now recommended within 3-4.5 hours of symptom onset.

“I’m already dead – don’t mourn for me,” were Tony Nicklinson’s last words before he died after seven years of unmitigated suffering. When Stephan Mayer’s patient, who was about 60 years old at the time of his stroke, left the hospital after beating incipient locked-in syndrome, he took up a new email address. Its username: notdeadyet.

References

Janjua N, Wartenberg KE, Meyers PM, & Mayer SA (2005). Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intravenous t-PA. Neurocritical care, 2 (3), 296-9 PMID: 16159079

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via olly / Shutterstock.

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Into the Looking Glass – Stroke, tPA, and Avoiding a Fate Worse Than Death http://brainblogger.com/2012/11/04/into-the-looking-glass-stroke-tpa-and-avoiding-a-fate-worse-than-death/ http://brainblogger.com/2012/11/04/into-the-looking-glass-stroke-tpa-and-avoiding-a-fate-worse-than-death/#comments Sun, 04 Nov 2012 12:00:15 +0000 http://brainblogger.com/?p=13318 Stroke, a major cause of death and the leading cause of adult disability, can leave victims unable to walk, talk, eat or take care of themselves. To treat stroke while it’s happening, the “clot-busting” drug tPA (tissue plasminogen activator) has been proven to save brains from damage and reduce or even completely avoid disability. Patients require a CAT-scan to assure diagnosis and the drug must be administered within 4.5 hours after onset of symptoms. In today’s medical environment, that shouldn’t be an overwhelming obstacle.

Although appropriate for almost 9 in 10 strokes — those that are ischemic, or due to blood clots — only a small fraction of potentially eligible patients, not more than about 4-8%, receive tPA.  Consider this:

It’s safe and effective…so few patients get it. As a drug for a major and life-threatening disorder, tPA was shown to be effective with a 11-13% absolute benefit (cancer drugs that provide a 2% absolute benefit are routinely approved).

It’s a one-time drug…yet so became the target of a muckraking campaign. Unlike drugs such as Vioxx, which were prescribed for daily use to masses of patients only to show unanticipated adverse effects, tPA for stroke is usually given once, intravenously. But its approval nevertheless incited journalists to campaign against it as dangerous and ineffective. Such charges lingered for years after post-approval studies confirmed the original results of randomized trials, which were supported not by the drug industry but by a branch of the National Institutes of Health.

Neurologists never had a drug to treat stroke before…so they were reluctant to use this one. Many neurologists might have been expected to be early adopters but initially only a few were enthusiastic. Neurologists were not accustomed to treating strokes as the emergencies they demonstrably are, and  many remained skeptical for years. Most have been by now been convinced, but tPA has been the most controversial drug ever used in neurology.

Emergency physicians were accustomed to using tPA… yet with stroke they didn’t want to. When the drug was first FDA-approved, ER doctors often used it for heart attack (most commonly due to clots, like stroke). But when it came to a brain disease, many (despite their reputation as cowboys in the ER) were fearful and concerned about their diagnostic acumen. A few created and many bought into the efforts to impugn tPA as overhyped by its manufacturer, Genentech, presumably in cahoots with the American Heart Association.

Stroke victims don’t know about tPA. Although controversies over the drug are now largely past, their legacy has been persistent lack of stroke awareness among the general public, with only a small minority of potential patients and their families or colleagues knowing the symptoms of stroke,  the importance of time-to-treatment, or the simple instruction (Call 911). So it is that, although FDA-approved for stroke since 1996, tPA today reaches only a fraction of nearly 800,000 new stroke victims annually in the United States. About 50% are potentially eligible.

References

Adeoye O, Hornung R, Khatri P, & Kleindorfer D (2011). Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke; a journal of cerebral circulation, 42 (7), 1952-5 PMID: 21636813

Zivin JA, Simmons J. tPA for stroke: the story of a controversial drug. New York: Oxford University Press; 2011.

Image via andkuch / Shutterstock.

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Depressed About Wrinkles? BOTOX Can Help http://brainblogger.com/2012/11/01/depressed-about-wrinkles-botox-can-help/ http://brainblogger.com/2012/11/01/depressed-about-wrinkles-botox-can-help/#comments Thu, 01 Nov 2012 11:00:23 +0000 http://brainblogger.com/?p=13554 The signs of aging can never seem to escape us: your eyes get puffier, your wrinkles lines extend in length, and the creases at the corners of your mouth deepen substantially. Soon, you remember a friend’s nonchalant remark that you seem to look angry all the time…even when you’re smiling.  Perhaps you are angry, both angry and sad that your youthful vigilance has come and gone all too quickly. Thankfully, there may be one treatment available that can offer a boost to your spirits: a recent study published in the Journal of Psychiatric Research reported that single treatment of age lines with botulinium toxin A (BTX-A or BOTOX) may alleviate depressive symptoms in patients who do not improve sufficiently on previous medication.

According to the World Health Organization (WHO), depression is one of the leading causes of disability, affecting as much as 121 million people worldwide. Although there are various effective treatments available, some patients register unsatisfactory responses to therapy causing their depression to enter into chronicity. Negative emotions such as anger, fear and sadness are prevalent facial expressions in depression that are associated with activation of the corrugator and procerus muscles in the glabellar region of the face. Injection of BTX-A to this facial region has been previously used to inhibit the activity of the corrugator and procerus muscles for the cosmetic treatment of frown lines. Unexpectedly, recipients of this treatment have also reported an increase in emotional wellbeing beyond the desired cosmetic benefit. Specifically, reduced levels of fear and sadness have been observed.

Taking these findings into account, the capacity for BTX-A to counteract negative emotions may also have clinical implications. To explore whether the attenuation of facial psychomotor features associated with depression may produce alleviation of affective symptoms, Wolmer et al. recently conducted a randomized controlled trial of BTX-A injection to the glabellar region as an adjunctive treatment of major depression. Thirty subjects, both men and women were included into the study and randomly assigned to treatment or placebo group. Subjects were included if their age ranged from ages 25-65 years old, had a diagnosis of on-going major depressive disorder according to the DSM-IV, and exhibited moderate to severe vertical glabellar lines during maximum voluntary frowning.

At baseline, the treatment and placebo group did not differ in any of the collected characteristics.  However, the treatment group showed a significant improvement in depressive symptoms compared to the placebo group at the 16-week follow-up mark, measured by the Hamilton Depression Rating Scale (HAM-D). Even after only one BTX-A treatment at the 6 week mark, BTX-A recipients’ depression scores were reduced on average by 47.1% compared to only 9.2% in placebo-treated participants. The authors concluded that a single treatment of the glabellar region with BTX-A may shortly accomplish a strong and sustained alleviation of depression in patients, although the mechanism of such effect has yet to be elucidated.

Although the mechanisms remain unclear, the authors do not attribute aesthetic benefit as a major contributor to mood improvement as they did not enroll patients into the study who were cosmetically concerned about their frown lines. Notably, treatment response also did not depend on a positive appraisal of the cosmetic change. However, the authors believe that it is possible that a more positive facial expression and improved feedback both from one’s own face in the mirror and from social interaction partners may have contributed to mood enhancement.

What does this mean for the future of BTX-A and its clinical applications? It is possible to extend these findings onto other muscles in the lower sections of the face (e.g. depressor angulis oris and mentalis muscles) and examine any mood-elevating effects.  Modulation of mood states with BTX-A may also be effective in the treatment of other clinical conditions involving negative emotions, like anxiety disorders. If true, findings from these studies would support the concept that facial musculature can not only express, but regulate mood states as well.

References

Gilmer WS, Trivedi MH, Rush AJ, Wisniewski SR, Luther J, Howland RH, Yohanna D, Khan A, & Alpert J (2005). Factors associated with chronic depressive episodes: a preliminary report from the STAR-D project. Acta psychiatrica Scandinavica, 112 (6), 425-33 PMID: 16279871

Lewis MB, & Bowler PJ (2009). Botulinum toxin cosmetic therapy correlates with a more positive mood. Journal of cosmetic dermatology, 8 (1), 24-6 PMID: 19250162

Sommer B, Zschocke I, Bergfeld D, Sattler G, & Augustin M (2003). Satisfaction of patients after treatment with botulinum toxin for dynamic facial lines. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 29 (5), 456-60 PMID: 12752511

Wollmer MA, de Boer C, Kalak N, Beck J, Götz T, Schmidt T, Hodzic M, Bayer U, Kollmann T, Kollewe K, Sönmez D, Duntsch K, Haug MD, Schedlowski M, Hatzinger M, Dressler D, Brand S, Holsboer-Trachsler E, & Kruger TH (2012). Facing depression with botulinum toxin: a randomized controlled trial. Journal of psychiatric research, 46 (5), 574-81 PMID: 22364892

Image via PhotographyByMK / Shutterstock.

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