New PD drug research leads to human trials

From Michael J. Fox Foundation newsletter:
http://www.michaeljfox.org/newsEvents_mjffInTheNews_pressReleases_article.cfm?ID=510




Vanderbilt-MJFF Partnership Yields Drug-Like Molecules Aimed at Improving Treatment of Parkinson's Disease

Researchers at Vanderbilt University Medical Center have achieved a milestone in the development of a potential new treatment for Parkinson’s disease that may improve on some of the limitations of current therapy.
Three drug-like molecules that act on a specific glutamate receptor in the brain are ready for the next stage of preclinical testing prior to entering human trials. The molecules were developed with major support from The Michael J. Fox Foundation for Parkinson’s Research (MJFF).

If all goes well in final preclinical testing, the molecules could be ready for clinical testing as soon as 2013, says Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery. “We are very excited to reach this major milestone and are eager to fully understand the extent of benefit that this new treatment strategy will have in patients suffering from Parkinson’s disease,” Conn said.

“Our Foundation is committed to advancing improved symptomatic therapies that could dramatically increase patients’ quality of life,” said MJFF CEO Todd Sherer, Ph.D. “The emergence of successful drug candidates from our partnership … points to the viability of a new model for drug development, one in which academic teams collaborating with forward-thinking funding partners can help keep the pipeline flowing with promising new agents.”

New models are urgently needed as pharmaceutical companies increasingly struggle to recoup their research investments in the development of new treatments. It can cost over a billion dollars to bring a drug to market. Some pharma firms already are downsizing their research operations as patent protection ends for some of their best-selling brand name products. Cuts in health care reimbursement for medications could bring even more financial challenges for the drugmakers.

Parkinson’s disease and the shortcomings of current treatments
An estimated 1 million Americans have Parkinson's disease, a progressive brain disorder characterized by resting tremor, rigidity and slowness of movement, as well as a battery of non-motor symptoms. It is caused by the death of nerve cells in a specific brain region that produce the neurotransmitter dopamine.

Dopamine replacement therapy, today’s gold standard treatment for Parkinson’s, relieves some motor symptoms of the disease, but over time it causes debilitating side effects such as involuntary, uncontrollable movements (dyskinesia). It is believed that dyskinesia is caused at least in part by the ebb and flow of dopamine levels in the brains of those receiving dopamine replacement therapy. Current Parkinson’s treatments also provide less and less benefit to patients as the disease worsens over the long term.
The new Vanderbilt compounds work in a fundamentally different way from dopamine replacement therapy, by bypassing the dopamine system altogether and instead modulating another of the brain’s neurotransmitters, glutamate. Conn and his colleagues have been working to activate a specific glutamate receptor called mGlu4.

The compounds are known as “positive allosteric modulators,” or PAMs. To increase mGluR4 activity while minimizing the likelihood of adverse effects, Conn’s team has taken a subtle approach to manipulating the mGluR4 receptor. “You can liken it to a dimmer switch on a light in your home, where you can turn up the gain of the receptor and its activity, or turn it down, without completely activating it or shutting it off,” Conn explained in a 2009 interview.

In their latest findings, the Vanderbilt researchers describe three PAMs that, when given systemically in a preclinical model of Parkinson’s disease, reach the brain and relieve motor symptoms, including rigidity and akinesia (a “freezing” of certain motor muscles).

NIH support

Conn’s colleagues in this effort include Craig Lindsley, Ph.D., co-director of the Center for Neuroscience Drug Discovery and Director of Medicinal Chemistry; Carrie Jones, Ph.D., the center’s director of Behavioral Pharmacology; Colleen Niswender, Ph.D., director of Molecular Pharmacology; J. Scott Daniels, Ph.D., director of Drug Metabolism and Pharmacokinetics; and Corey Hopkins, Ph.D., research assistant professor of Pharmacology and Chemistry.

Their work has been supported since 2007 by more than $4 million, largely awarded under MJFF’s LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) initiative, which assembles teams of researchers with the various expertise required to bring a particular project to fruition, and to do so in as efficient and streamlined a way as possible. Conn’s speedy results are an example of a successful LEAPS project in action.

Conn’s work on Parkinson’s disease actually began in the 1990s when he was at Emory University. That research was conducted as part of a Morris K. Udall Center of Excellence in Parkinson's Disease Research supported by the National Institute of Neurological Disorders and Stroke (NINDS).
In 2010, he and his colleagues began a partnership with a new NINDS Udall Center at Emory to explore additional allosteric modulators as potential treatments for Parkinson’s disease.

"A primary goal of the NINDS Udall Centers program is to foster translation of research observations into improved treatments for Parkinson’s disease,” said Beth-Anne Sieber, Ph.D., a program director at NINDS. “We are pleased to support Dr. Conn’s discovery efforts as part of this program.”
The Vanderbilt-Fox Foundation partnership is an example of how academic medical centers are helping to fill the “drug pipeline” with new agents that potentially will dramatically improve the health of millions of patients worldwide.

Personal update 9-27-11

http://www.youtube.com/watch?v=Hu_xj1U9ft0
Here's my latest video update.

Sinemet causing nausea

I took two Sinemet tablets today, along with Ardane. Those are for my PD symptoms. Then I took some Rx pain killers for the disk problems in my upper back. Mid-day I had excellent control of my hands for piano practicing. Not perfect, but much better than usual. I could play trills and turnarounds for the first time in years. I could not play quickly-repeating, rhythmic chords such as in the Chopin 'Military Poloniase', unfortunately. Still, the control and facility I did have was exhilarating and fun! I played for a couple of hours. It's nice to know that the nerves and muscles are still hooked up. I guess it's just the neurotransmitters that are missing, or are in short supply. It's such a weird disease. Whether it's PD or Lyme, it's really crazy makung and frustrating.

Later on, around 9PM, I started feeling shaky again, so I took another Sinemet. It was on a fairly empty stomach. I felt pretty immediately nauseated, within the hour. Hot flashes, low body temp (95.2), dizzy. An hour later it passed, after eating some chicken. I suspect it was the sinemet, but it sure felt funky.

Personal video update

First video posting from iPad 2:
http://www.youtube.com/watch?v=1AO78VbenOE
Bob

Using Bone Marrow to Protect the Brain

Using Bone Marrow to Protect the Brain: Stem Cell Technology Begins Clinical Trial for Lou Gehrig's Disease

ScienceDaily (Sep. 21, 2011) — The ability to produce neuroprotectors, proteins that protect the human brain against neurodegenerative disorders such as Parkinson's and ALS, is the holy grail of brain research. A technology developed at Tel Aviv University does just that, and it's now out of the lab and in hospitals to begin clinical trials with patients suffering from amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

See article
http://www.sciencedaily.com/releases/2011/09/110920080351.htm

Virus destroys Parkinson's symptoms

Parkinson's disease is a progressive disorder of the nervous system that affects movement. It develops gradually, and often starts with a barely noticeable tremor in one hand. While tremors may be the most well-known sign of Parkinson's disease, the disorder also commonly causes a slowing or freezing of movement...

Read article here:

http://austin.ynn.com/content/health/280432/your-health--virus-destroys-parkinson-s-symptoms

Researchers Find New Bacterium Causing Tickborne Illness Ehrlichiosis in Wisconsin, Minnesota

August 4, 2011

A new tickborne bacterium infecting humans with ehrlichiosis has been discovered in Wisconsin and Minnesota. It was identified as a new strain of bacteria through DNA testing conducted at Mayo Clinic. The findings appear in the Aug. 4 edition of the New England Journal of Medicine.

Doctors at Mayo Clinic, the Centers for Disease Control and Prevention (CDC), the University of Minnesota, the University of Wisconsin, and state and local health departments say the new species from the Ehrlichia genus can cause a feverish illness in humans. The new bacterium, not yet named, has been identified in more than 25 people and found in black-legged ticks, also known as deer ticks (Ixodes scapularis), in Minnesota and Wisconsin. Researchers used culture and genetic analyses.

“Before this report, human ehrlichiosis was thought to be very rare or absent in Minnesota and Wisconsin,” says Bobbi Pritt, MD, a Mayo Clinic microbiologist and director of the Clinical Parasitology and Virology Laboratories who helped coordinate the multi-agency team. “Therefore, physicians might not know to look for Ehrlichia infections at all.”

Ehrlichia infect and kill white blood cells and may cause fever, body aches, headache and fatigue. More severe disease may involve multiple organs such as the lungs, kidneys and brain and require hospitalization. Ehrliochosis rarely results in death.

All four patients described in the New England Journal of Medicine article suffered fever and fatigue. One patient, who had already received a bilateral lung transplant, was hospitalized briefly for his illness. All four patients recovered following antibiotic treatment with doxycycline, the drug of choice for treating ehrlichiosis. Although more than 25 cases have been identified, many more have likely been missed or unreported, Pritt says.

The investigation began after Carol Werner, then a technologist at Mayo Clinic Health System’s Eau Claire hospital, noted an abnormal Ehrlichia Polymerace Chain Reaction (PCR) result in 2009 and raised the first red flag. Mayo Clinic then began investigating with the CDC, the universities and several public health departments. The Minnesota Department of Health last year put out a health advisory alerting people that it and its Wisconsin counterpart were seeing increasing reports of ehrlichiosis in humans.

“As the deer tick population continues to spread and increase across Wisconsin, we are likely to see increasing incidence of this new infection, just as we have seen with Lyme disease and anaplasmosis which are transmitted by the same tick species,’’ says co-author Susan Paskewitz, PhD, an entomologist at the University of Wisconsin-Madison.

To date, thousands of blood samples from across the United States have been screened by Mayo Clinic laboratory technologists, and the bacterium has been detected only in specimens collected from Wisconsin and Minnesota. Thousands of ticks across the country have also been analyzed, and only those from the two states have been carriers.

Because the bacterium is likely transmitted through the bite of an infected tick, Pritt cautions that people should apply insect repellent and wear pants and long-sleeved shirts when active outdoors.

Doctors need to know to test for ehrlichiosis in the two states so the diagnosis is not missed. However, traditional blood antibody tests may offer misleading results and fail to accurately identify the new species. A specific antibody test for the new bacterium has been developed by the CDC but isn’t widely available. Instead, a molecular blood test that detects DNA from the new Ehrlichia species is the preferred method for detecting this disease in symptomatic patients.

When testing for this new Ehrlichia species, physicians should also consider testing for other tickborne diseases, such as Lyme disease, babesiosis and anaplasmosis, all prevalent in Minnesota and Wisconsin, Pritt says.

Genetically, the new bacterium bears closest similarity to another species of Ehrlichia -- E. muris -- that infects small rodents and deer in Eastern Europe and Asia. E. muris rarely infects humans, and no cases have been reported in North America.

From: Infection Control Today

http://www.infectioncontroltoday.com/news/2011/08/researchers-find-new-bacterium-causing-tickborne-illness-ehrlichiosis-in-wisconsin-minnesota.aspx

Herpes Virus Linked to Alzheimer's

Laboratories at the University of New Mexico (UNM), Brown University, and House Ear Institute (HEI) have developed a new technique to observe herpes simplex virus type 1 (HSV1) infections growing inside cells. HSV1, the cause of the common cold sore, persists in a latent form inside nerve cells. Re-activation and growth of HSV1 infections contribute to cognitive decline associated with Alzheimer’s disease. Details are published in the March 31 issue of PLoS ONE magazine from the Public Library of Science.

"Herpes infects mucous membranes, such as the lip or eye, and generates viral particles," submits study principal investigator Elaine Bearer, MD, PhD, the Harvey Family Professor and vice chair for research, Department of Pathology, UNM School of Medicine. "These viral particles burst out of the cells of the mucous membrane and enter sensory nerve cells where they travel inside the nerve toward the brain. We now can see this cellular transportation system and watch how the newly formed virus engages cellular APP on its journey out of the cell."

Tagging herpes virus inside cells with green fluorescent protein, scientists used live confocal imaging to watch HSV1 particles emerge from infected cells. Newly produced viral particles exit the cell nucleus and then bud into cellular membranes containing amyloid precursor protein (APP). Electron microscopy at HEI detailed the ultrastructural relationship between HSV1 particles and APP.

This dance between viral particles and cellular APP results in changes in cellular architecture and the distribution of APP, the major component of senile plaques found in the brains of Alzheimer's disease patients. Results from this study indicate that most intracellular HSV1 particles undergo frequent, dynamic interplay with APP, which facilitates viral transport while interfering with normal APP transport and distribution. This dynamic interaction reveals a mechanism by which HSV1 infection leads to Alzheimer's disease.

In developed countries such as the U.S., approximately 20 percent of children are infected with HSV1 prior to the age of five. By the second and third decades of life, as much as 60 percent of the population is infected, and late-in-life infection rate reaches 85 percent.

Symptoms of primary HSV1 infection include painful blisters of the mouth, lips or eyes. After infection, HSV1 persists in nerve cells by becoming latent. Upon re-awakening, new viral particles are made in the neuron and then travel back out its pathways to re-infect the mucous membrane. Many infected people experience sporadic episodes of viral outbreaks as the well-known recurrent cold sore.

"Clinicians have seen a link between HSV1 infection and Alzheimer's disease in patients, so we wanted to investigate what might be going on in the body that would account for this," adds Dr. Shi-Bin Cheng, post-doctoral associate, Department of Pathology and Laboratory Medicine, Alpert Medical School, Brown University. "What we were able to see in the lab strongly suggests a causal link between HSV1 and Alzheimer's Disease."

"It’s no longer a matter of determining whether HSV1 is involved in cognitive decline, but rather how significant this involvement is," Bearer asserts. "We’ll need to investigate anti-viral drugs used for acute herpes treatment to determine their ability to slow or prevent cognitive decline."

Researchers recommend people treat a cold sore as quickly as possible to minimize the amount of time the virus is actively traveling through a person’s nervous system. The faster a cold sore is treated, the faster the HSV1 returns to a dormant stage.

From:
http://www.infectioncontroltoday.com/news/2011/04/researchers-link-herpes-to-alzheimers-disease.aspx

Researchers Say Local Antibiotic Therapy Stops Lyme Disease

Lyme disease is a dangerous disease which is transmitted by ticks. Blood-sucking ticks ingest the agents that cause the disease – bacteria of the species Borrelia burgdorferi and its relatives – during a blood meal, and subsequently transmit them to the next victim they feast on, often a person. It is estimated that, in Western Europe, up to half of all ticks carry the bacteria. Although the early symptoms of the illness are quite mild, if left untreated, it can result in serious damage to the skin, the joints, the heart and the nervous system, and effective therapy becomes very difficult.

A team of researchers led by the veterinary bacteriologist professor Reinhard Straubinger at Ludwig-Maximilians Universität (LMU) München has now shown, in an animal model, that application of a gel containing the antibiotic azithromycin to the site of the bite rapidly terminates the infection. The efficacy of this local antibiotic therapy for the treatment of borreliosis in humans is now being tested in a Phase III clinical trial. In the meantime, though, patients must still undergo antibiotic treatment for several weeks and, in many cases, the drug must be administered intravenously – which is distressing not only for children. Furthermore, treatment measures are often initiated on suspicion, because the bacteria are not detectable in the blood soon after one has been bitten by an infected tick.

"Our approach simply involves applying a transparent, self-adhesive plaster to the site of the wound," says Straubinger. "Because the plaster contains very little antibiotic, the effects are localized and side-effects are negligible."

Reference: Knauer J, et al. Evaluation of the preventive capacities of a topically applied azithromycin formulation against Lyme borreliosis in a murine model. Journal of Antimicrobial Chemotherapy online, Sept. 15, 2011.

Book about handling chronic illness

A colleague of mine who is also dealing with chronic, painful and debilitating illness just gave me a reference that might be worth checking out:

Author: Toni Bernhard

Title: How to be sick: A Buddhist-inspired Guide for the Chronically Ill and Their Caregivers.

http://www.amazon.com/How-Sick-Buddhist-Inspired-Chronically-Caregivers/dp/0861716264

Continuing to Lose Weight

Not sure why I'm down to 124. Possibly because shopping is difficult since the back pain and perhaps the antibiotics and/or Lyme have messed with my absorption. I started taking digestive enzymes a couple of weeks ago. Normal weight for me is 135-140.

Lyme study needs subjects

This email is to let you know about a Lyme Disease research project going on the the San Francisco Bay Area that needs more Lyme patients as participants. Many of our established members have already heard about this already, but we've had a lot of new people sign up recently who might be good candidates.

The study is being conducted by a health care practitioner who treats Lyme patients in the bay area. She's teamed up with some researchers at Stanford University to conduct a study examining the accuracy of various Lyme Disease tests. This is a Lyme-Literate and CALDA sponsored study. The results will benefit all Lyme patients.

To see if you qualify for the study and to sign up, please see the instructions on the study recruitment flyer, found in the files section of the LEAPS meetup website:

http://bit.ly/n9K

I recenly heard from the investigators they're almost done with the study, they just need a few more people, so please pass this on to everyone you know!

My latest commentary about computers. The Desktop is Dead.

Well, I've been using an iPhone and iPad most exclusively for my computing needs for the last six months or so. This is probably because I have been mostly incapable of sitting in the chair for any length of time due to the various symptoms. But it's also because I have become fond of these devices. I can take them wherever I want, whether walking around, lying down in bed or sitting in a comfy chair, etc. Makes computing so much easier.

In any case, tonight I had a project to do which consisted of consolidating a bunch of e-mails on my desktop iMac and creating a chart out of them in Microsoft Word. It should have been a very simple project. Should not be difficult, right? Well, it took me about two hours to do it. Unbelievable.

I had not used my new fancy iMac for about two weeks. I am running Parallels with Windows 7, running under OS X. The computer has been mostly in sleep mode over the past few weeks but it had been 'on' some of the time, so conceivably it could have updated itself and been ready to roll. In any case, I powered it up and sat down ready to do some quick work on it and get to bed at a timely hour. Whether it is the electronic goblins, the Muses who are working their wiles against me, or just a ridiculous state of complexity of microcomputers, I don't know, but the stark contrast to the ease with which iOS devices (the iPad in the iPhone) work became so obvious to me that I almost pulled my hair out and threw my computer, as brand-new and shiny as it is, out the window.

Now admittedly, I am dealing with a pinched nerve in my neck and it's giving me major back pain so I am not a particularly happy camper, and I have this incredible tremor from the Parkinson's disease or whatever. So I am not long on patience right now. But still, I am a clever guy, and I know how to get around computers and have written many books about them over the years. So usually I can just skin a cat one way or the other and do the 'computer whisperer' thing, and get stuff to work.

Suffice it to say I had about 20 dialog boxes come up over the course of the time I was working, maybe more. Did I want to update iTunes? How about security updates for OS X. Did I want to? Windows had some updates to do, too. Ad-Aware needed urgently to update. The computer slowed to a crawl a few times with the hard drive getting continuous disc hits, and the CPU pegged despite the fact that I was intentionally doing next to nothing. I had to close all the browser windows I had open and methodically shut down all kinds of stuff like the Apple Mail program and Outlook in order to get the CPU out of the gutter. I eventually just decided to shut down the Windows 7 virtual machine and Parallels, then reboot OS X. So, I had to reboot two operating systems which took another about 15 minutes to do. This was in part because various programs failed to shut down even though I told the operating systems to shut down. And it wasn't just Windows, it was also OS X, too. Mail would not shut down, for example, so I had to force quit it.

After rebooting, the scanner that I was trying to use with Paperport could not be found. In an hour's worth of trying to reconnect it through software and hardware tricks, I did not succeed. I tried another scanner. That didn't work either. Flash wanted to be updated, Java wanted to be updated. The NTFS driver that I have for Mac OS X so I can use my external hard drive timed out and needed to be repurchased. Many another dialog boxes and error messages, things not found, and so forth presented themselves from time to time.

Next, I realized how frustrating it is to actually work with the mouse. I have both a mouse and the magic trackpad connected to the iMac. But with the 27-inch screen on the iMac, getting from one corner to the other corner really takes some hand work. I had to close programs and aim at the little red X or the little red dot in the corner of the application window. Numerous times I missed. Or, I was trying to select a bunch of text and then had to right click on it or remember the right keyboard control sequence for a copy and paste, which happens to be different between Windows and OS X. So I was busy navigating between apps, with a lot of dexterity required. I overshot a few times and application documents disappeared, and so forth. You know, the usual.

Geeze, all I wanted to do was copy some text from some e-mails and put them in another e-mail or in a Word document so I can send it to somebody.

Once I saved the document, it went into some remote folder somewhere, so that I had to navigate to that. Then right click on it and choose Send to > Mail recipient, and then that opened up Word to create a new mail document, and then I had to navigate my recipient list, and so forth. Eventually after rooting around for a while, I got the e-mail sent. The entire endeavor took about two hours. It was excruciating.

I was just saying to a friend today that computers are like relationships: If you have too many of them around you're really asking for trouble. They all take maintenance. I suggest that if you are considering having more than one computer in your life, forget about it. Each one takes so much maintenance that it's not worth having more than one. And once you become familiar with one operating system or one set of applications or one interface or one keyboard or whatever, switching between them is too much mental overhead.

Desktop personal computers are just too damn complicated. Period. I was more than happy to get back to my iPad so I could dictate this rant. Sure, it takes several steps, dictating into Dragon, and double clicking the Home button to switch back and forth between that and BlogPress, but big deal. It's not too difficult, and it actually works.

As much as I hate the idea of having everything on 'the Cloud', and losing control over my data, where it is, who's looking at it, and losing control over my applications, I have to say that it's probably going to be a giant breakthrough when we no longer have to maintain, update, replace, repurchase, purchase new, or whatever all of our applications, all of the time. Updating our operating systems, our virus protection programs, our various other malware protection programs is a gigantic pain in the butt.

Viva le tablet and le Cloud!

Comments?