NEW DRUG DELIVERY CAPSULE MAY REPLACE INJECTIONS

Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.

To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

"This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug," says Giovanni Traverso, a research fellow at MIT's Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which appears in the Journal of Pharmaceutical Sciences.

Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn's disease. This class of drugs, known as "biologics," also includes vaccines, recombinant DNA, and RNA.

"The large size of these biologic drugs makes them nonabsorbable. And before they even would be absorbed, they're degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive," says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.

Safe and effective delivery

Scientists have tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.

Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimeters long and 1 centimeter in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimeters long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals' blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

"The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration," Traverso says. "For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency."

"This is a very interesting approach," says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. "Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe."

Further optimization

This approach could also be used to administer vaccines that normally have to be injected, the researchers say.

The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

New Guidelines For Treating Painful Neuropathy

You know by now that when an article talks about diabetic neuropathy, unless it's discussing blood sugars or other specific diabetes issues, you can more or less apply the information to all forms of  sensory neuropathy. The causes may be different but the symptoms pretty much apply to all. Today's article comes from depressionforums.org (see link below) and discusses the very interesting guidelines issued by the American Academy of Neurology. It's good to see that they advise the use of the traditional neuropathy treatments "if clinically appropriate". This article was written in April, 2011 and therefore a year before Pfizer withdrew Lyrica (Pregabalin) promotion for diabetes and HIV-related neuropathy - the message is that doctors should always prescribe drugs "if clinically appropriate" and not just as a matter of course.

New AAN Guidelines on Painful Diabetic Neuropathy
Susan Jeffrey April 11, 2011 (Honolulu, Hawaii)

 — The American Academy of Neurology has released new guidelines on the treatment of painful diabetic neuropathy (PDN).

The document provides evidence-based guidance on use of a range of pharmacologic agents, including anticonvulsants, antidepressants, opioids, and others, as well as nonpharmacologic treatments, such as transcutaneous electrical nerve stimulation (TENS) and magnetic field treatment.

"We were pleased to see so many of the pain treatments had high-quality studies that support their use," said Vera Bril, MD, from the University of Toronto, Ontario, Canada, lead author of the guidelines. "Still, it is important that more research be done to show how well these treatments can be tolerated over time, since diabetic nerve pain is a chronic condition that affects a person's quality of life and ability to function."

The guidelines are published online April 11 in Neurology and were presented here at the American Academy of Neurology 63rd Annual Meeting. They were developed in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation; the document will appear in the April issues of their respective journals, Muscle and Nerve and PMR.

Unreported, Untreated
It is estimated that PDN affects 16% of the more than 25 million people who have diabetes in the United States, the authors point out. The condition is "often unreported and more often untreated, with an estimated 2 out of 5 cases not receiving care," Dr. Bril noted.

"As we emphasize the use of evidence-based guidelines to treat different disorders, it becomes clear that this field is very confusing because of the volume of literature," Dr. Bril told a press briefing here. "So the guidelines have been developed and will provide a framework for physicians to use when treating their patients. Physicians can understand what the evidence is for the treatments they'll use; when there is evidence, when there isn't, or when the evidence is negative."

The process started in 2007, with more than 2200 papers on PDN; of these, 463 were deemed relevant to the guidelines. Author teams reviewed these papers and identified 79 considered "highly pertinent" to the guideline. Each of these reports was rated by teams of 2 with regard to class of evidence for effectiveness, and disagreements were arbitrated by a third member.
The only drug to earn a "Strong Evidence, Level A" rating was pregabalin, but several drugs and nonpharmacologic interventions met criteria for "Moderate Evidence, Level B" endorsement.
That only 1 drug met this level of evidence was a bit of a surprise, Dr. Bril noted. "One of the big factors that moved a study from class I to class II is that you needed at least 80% of the people in the study to complete the study," Dr. Bril said, and 2 class I studies were required for a Level A recommendation.

"I can tell you there was discussion internally about the rules because of the way it fell out, but it would be a little strange to be changing your rules for guidelines because of the findings in 1 guideline process," she said. "The others are Level B mostly because they didn't get 80% completing their studies."

The level of evidence is not driven by the effect size of the drug, she noted. "So pregabalin has a small effect on pain, but the studies were class I, and you could say people tolerated the treatment and stayed in" the pregabalin studies, Dr. Bril added. "So you can't make assumptions and change the rules because of what you're finding."
They also provide the recommended doses of agents considered useful in the document.

Strong Evidence (Level A)

• Pregabalin should be offered "if clinically appropriate."

Moderate Evidence (Level B)

• Anticonvulsants gabapentin and sodium valproate should be considered for PDN treatment. The authors note though that because valproate is potentially teratogenic, it should be avoided in diabetic women of child-bearing age, and due to its potential adverse effects of weight gain and worsening of glycemic control, "this drug is unlikely to be the first treatment choice for PDN."
• Anticonvulsants oxcarbazepine, lamotrigine, and lacosamide should probably not be considered.
• Antidepressants amitriptyline, venlafaxine, and duloxetine should be considered; however, "data are insufficient to recommend one of these agents over the others," they note.
• Opioids dextromethorphan, morphine sulphate, tramadol, and oxycodone should be considered for the treatment of PDN, they note. Again data were insufficient to recommend one of these over the others.

They note that the use of opioids for chronic nonmalignant pain has "gained credence over the last decade due to the studies reviewed in this article." Both tramadol and dextromethorphan were associated with substantial adverse events, including sedation with both agents and nausea and constipation with tramadol. The use of these agents can also be associated with development of novel pain syndromes, such as rebound headache, the authors note, and long-term use can lead to tolerance and frequent escalation of dose.

• For other pharmacologic interventions, they recommend that capsaicin cream and isosorbide dinitrate spray be considered to manage PDN, although they note that many patients can be intolerant to the adverse effects of capsaicin, which include burning pain on contact with warm or hot water or in hot weather.
• Clonidine, pentoxifylline, and mexiletine, on the other hand, should "probably not" be considered for use.
• For nonpharmacologic treatments, they recommend that use of TENS be considered but "probably not" electromagnetic field treatment, low-intensity laser treatment, or Reiki therapy.

Weak Evidence (Level C)

• They found weak evidence that adding venlafaxine to gabapentin may provide a better response and that the Lidoderm patch may be considered to treat PDN.

Insufficient Evidence (Level U)

• The authors found insufficient evidence to "support or refute" use of the anticonvulsant topiramate; the antidepressants desipramine, imipramine, and fluoxetine; or the combination of nortriptyline and fluphenazine.
• Similarly, there was insufficient evidence either way on the use of vitamins and α-lipoic acid or the combination of amitriptyline with electrotherapy for treatment of this condition.

Placebo Effect
In their summary document, the authors point out as "notable" that the placebo effect varied from 0% to 50% pain reduction in the studies reviewed for this guideline.
"The panel recognizes that PDN is a chronic disease and that there are no data on the efficacy of the chronic use of any treatment, as most trials have durations of 2 to 20 weeks," they write. "It is important to note that the evidence is limited, the degree of effectiveness can be minor, the side effects can be intolerable, the impact of improving physical function is limited, and the cost is high, particularly for novel agents."
Neurology. Published online April 11, 2011.

 Author(s)

Susan Jeffrey

Susan Jeffrey is the news editor for Medscape Neurology & Neurosurgery. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians.

http://www.depressionforums.org/depressive-diseases-health-disorders/178-chronic-pain-depression/2275-new-aan-guidelines-on-painful-diabetic-neuropathy

New Ways To Repair Nerve Pathways

Today's post from (see link below) looks at new discoveries about dendrites, which are a component of nerve cells which receive information from the brain. It explains that these dendrites are capable of rapid re-growth after injury. before it was thought that axons (part of the cell which sends information to other cells) were the only cell components capable of regeneration. Discovering that dendrites can do it even more quickly and independently of axons may lead to treatments which can promote this activity and thus repair nerve damage more effectively. Sure, all this investigation has been done via fruit flies but the science always has to be established first before it can be applied to human injury - fascinating.

New Pathway for Neuron Repair Discovered  
Jan. 9, 2014 Story Source: The above story is based on materials provided by Penn State.

— Penn State University molecular biologists have discovered a brand-new pathway for repairing nerve cells that could have implications for faster and improved healing. The researchers describe their findings in a paper titled "Dendrite injury triggers DLK-independent regeneration," which will be published in the 30 January 2014 issue of the journal Cell Reports. These findings demonstrate that dendrites, the component of nerve cells that receive information from the brain, have the capacity to regrow after an injury.

Previous studies using many models have shown that when nerve cells, or neurons, are injured they repair the damage through regrowth of axons, the component of a neuron that sends information to other cells, explained co-author Melissa Rolls, associate professor of biochemistry and molecular biology at Penn State. "For example, if you break your arm and the bone slices some axons, you may lose feeling or movement in part of your hand. Over time you get this feeling back as the axon regenerates."

Using the fruit fly (Drosophila) as a model system, the researchers took what Rolls calls a "radical approach," cutting off all of the dendrites in neuron cells. "We wanted to really push the cells to the furthest limit," she said. "By cutting off all the dendrites, the cells would no longer be able to receive information, and we expected they might die. We were amazed to find that the cells don't die. Instead, they regrow the dendrites completely and much more quickly than they regrow axons. Within a few hours they'll start regrowing dendrites, and after a couple of days they have almost their entire arbor. It's very exciting -- these cells are extremely robust."

Moreover, it appears that dendrite regeneration happens independently of axon regeneration. When Rolls and her colleagues blocked the key signaling molecules that are required for axon regeneration in all animals, they found that dendrites were unaffected and continued to regrow. "This means that, not only do these neurons have an incredible ability to generate, they have two different regeneration pathways: one for axons and one for dendrites," she said. "Because it has not even been clear that dendrites can regenerate, it's a complete open question about what might be involved in that process. The next step will be to look for markers for dendrite regrowth -- proteins that are required or genes that are turned on in the process -- so we can learn more about what's going on during dendrite repair. We don't even know in what scenarios dendrite regeneration might happen in people yet because no one has known that it exists."

The implications for human health -- although a long way down the road -- are important, Rolls said. For example, in the case of stroke, when a region of the brain suffers blood loss, dendrites on brain cells are damaged and can be repaired only if blood loss is very brief. Otherwise, it is thought those brain cells die. But if those cells are able to regenerate dendrites, and if scientists learn how dendrite regrowth happens, researchers may be able to promote this process.

"We've provided some cause for hope when it comes to neuron damage," Rolls said. "This is optimistic work we are doing. It's just great to know there is this whole other pathway for survival that no one has even looked into before."

 http://www.sciencedaily.com/releases/2014/01/140109132422.htm

Gene Therapy Offers New Hope For Treatment Of Peripheral Neuropathy

ScienceDaily (June 1, 2007) (so not exactly new!)

— Researchers from the University of Pittsburgh School of Medicine report that they have successfully used gene therapy to block the pain response in an animal model of neuropathic pain, a type of chronic pain in people for which there are few effective treatments.



Neuropathic pain is the result of damage to nerve fibers caused by injuries or diseases, such as diabetes and cancer. These damaged nerve fibers continue to send signals to pain centers in the brain even after the surrounding tissue has healed. Unfortunately, neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better over time. For some people, it leads to serious, long-term disability and dependence on pain medications that have a variety of unwanted side effects, including addiction.

The Pitt research team, led by Joseph Glorioso, III, Ph.D., chair of the department of biochemistry and molecular genetics, University of Pittsburgh School of Medicine, used a genetically engineered herpes simplex virus (HSV) to deliver the gene for part of the human glycine receptor (GlyR), a receptor found primarily on the surface of nerve cells in the spinal cord and the lower brain but not in the nerves in the limbs, to the paws of rats. A group of control rats received only the HSV vector without the inserted gene.

After the delivery of the therapeutic gene or empty vector (for the control group), the researchers injected the same paws of each rat with formalin, an irritant known to simulate the symptoms of a peripheral neuropathic pain at the site of injection. Following formalin injection, the rats were then given an injection of glycine to activate the GlyR receptor.

Both control and GlyR-HSV-infected rats showed a typical pain response to formalin. However, the application of glycine eliminated the pain response in GlyR-HSV infected animals, while it had no effect on animals infected with vector only. This alleviation of the pain response in GlyR-HSV-treated mice was reversed by the subsequent addition of low concentrations of strychnine, a strong GlyR-specific inhibitor, or antagonist.

According to Dr. Glorioso, these findings suggest that HSV-directed expression of GlyR in peripheral neurons and subsequent selective activation by glycine has the potential to be used therapeutically not only for neuropathic pain management but a variety of pain syndromes.

"The inability to effectively manage neuropathic pain associated with injuries and illnesses is a growing national and international problem. Gene therapy offers a more targeted, less toxic approach for effectively managing this condition. It also is our hope that targeted transgene delivery of GlyR may have even broader implications for managing a number of chronic pain syndromes, including pain resulting from shingles, arthritis and cancer," explained Dr. Glorioso.

These findings are being presented at the 10th annual meeting of the American Society of Gene Therapy, being held May 30 to June 3 at the Washington State Convention & Trade Center, Seattle.

In addition to Dr. Glorioso, others involved in the study included Michael Cascio, Ph.D., James Goss, Ph.D., David Krisky, M.D., Ph.D., and Rahul Scrinivasin, M.D., Ph.D., all with the department of molecular genetics and biochemistry, University of Pittsburgh School of Medicine.

New Growth

What sheer delight .... my beautiful two year old Elder (Sambucus Canadensis) returned with good and healthy folage this spring. last year she was devoured within days by a monstrous super-worm who webbed, nested on, and then ate the entire plant leaving but a skeleton. I didn't know if she would make it, or what to do. So you can imagine my double delight when I spotted, at my feet, a baby! Oh joy! I can't wait for flowers ... and dare I wish for berries?
I suppose the newborn Elder makes up for my S. Nigra not returning :(. I was told it was just as hearty. There were no pests on that one, oddly enough.

Below, is a beautiful display of new coming out of old. I often read instructions to cut back my woody plants before winter; Sage, Lavender, and Rosemary. Well the latter dies no matter what I do, but thee Sage and Lavender grow directly out of the remaining stem. They have unanimously died each time in the past where I cut them back. This Sage even over wintered in a pot on my deck amazingly enough, especially for a first year plant. I love her perfect illustration of renewal.

New Drugs To Be Targeted At Pain Receptors Deep In The Nerve Cell

Today's post from sciencedaily.com (see link below) may at first sight seem a little difficult to understand but basically, when the body experiences pain, there are pain receptors on the surface of nerve cells that identify it and transmit the information further and let you feel that pain. If the pain is extreme, sometimes these pain receptors retreat to the nucleus of the cell, as if it's 'safer' there. Pain relieving drugs are designed to block the pain signals in the receptors at the surface of the cell but if the receptors have migrated to the nucleus then the drugs don't have any effect. This knowledge enables researchers to design pain-relieving drugs that can penetrate the nerve cell to the nucleus and thus block the signals from reaching the receptors. They can then 'safely' return to the surface of the cell. At least that's the theory and although it may seem like double-dutch to most of us, sometimes it's interesting to know in which direction the scientists are going.
 

Location may be key to effectively controlling pain
Date:February 3, 2016 Source:McGill University
 
In real estate, location is key. It now seems the same concept holds true when it comes to stopping pain. New research published in Nature Communications indicates that the location of receptors that transmit pain signals is important in how big or small a pain signal will be -- and therefore how effectively drugs can block those signals.

Blocking pain receptors in the nucleus of spinal nerve cells could more effectively control pain than interfering with the same type of receptors located on cell surfaces. The scientists also found that when spinal nerve cells encounter a painful stimulus, some of the receptors will migrate from the cell surface into the nucleus.

A team of researchers led by McGill University's Director of Anesthesia Research Terence Coderre and Karen O'Malley at Washington University in St. Louis, found that rats treated with investigational drugs to block the activity of the receptors in the nucleus soon began behaving in ways that led them to believe the animals had gotten relief from neuropathic pain. According to Prof. Coderre, "drugs that penetrate the spinal nerve cells to block receptors at the nucleus were effective at relieving pain, while those that don't penetrate the nerve cells were not. Rats with nerve injuries had less spontaneous pain and less pain hypersensitivity after blocking receptors at the nucleus, while the pain sensitivity of normal rats was not affected."

Location is key
Scientists have been studying glutamate receptors in the pain pathway for decades. What's new, Coderre explained, is that these most recent experiments -- in cell cultures and rats -- demonstrate that the location of the receptor in the cell has a major effect on the cell's ability to transmit pain signals.

The researchers focused mainly on nerve cells in the spinal cord, an important area for transmitting pain signals coming from all parts of the body.

"We'll now focus our research at determining what events cause the glutamate receptors to migrate to the nucleus, and how to produce drugs that more specifically block glutamate receptors only at the nucleus," added Coderre.

Story Source:

The above post is reprinted from materials provided by McGill University. The original item was written by Cynthia Lee. Note: Materials may be edited for content and length.

Journal Reference:
Kathleen Vincent, Virginia M. Cornea, Yuh-Jiin I. Jong, André Laferrière, Naresh Kumar, Aiste Mickeviciute, Jollee S. T. Fung, Pouya Bandegi, Alfredo Ribeiro-da-Silva, Karen L. O’Malley, Terence J. Coderre. Intracellular mGluR5 plays a critical role in neuropathic pain. Nature Communications, 2016; 7: 10604 DOI: 10.1038/NCOMMS10604

http://www.sciencedaily.com/releases/2016/02/160203111018.htm

New Cream In Development To Reverse Neuropathy A Big Claim

Today's short post from cardiovascularbusiness.com (see link below) is a version of many other such articles that have suddenly appeared on the internet in the last week, announcing the development of a new trans-dermal ointment to treat neuropathy. It's short because frankly, there's not much to report and yet it has caught the imagination of the neuropathy Net. Basically, a sort of ganglioside (a molecule important in immunology) called GM3 has been found that contributes to neuropathic pain. The theory is that an ointment can be developed to reduce GM3 in the body, thus reducing neuropathy symptoms. The difference between this finding and other developments is that they claim that this can reverse the nerve damage instead of just treating the symptoms. That's a pretty big claim but because it's years away from becoming anything that will appear on doctors' prescription pads, or even human trials, so we can only wait and see. However, we're fairly used to this sort of 'breakthrough' news aren't we? A pinch of salt anyone!

Researchers develop ointment to reverse neuropathy in diabetic patients
Sep 15, 2016 | Katherine Davis

 More than 25 percent of type-2 diabetes patients suffer from neuropathy, a condition that causes numbness and nerve pain in the feet. But new research from Northwestern University has found a way to reverse the condition.

The study, published in Molecular Pain, gives hope to thousands of diabetic patients whom have high levels of GM3, a type of ganglioside that contributes to constant pain in their feet.

"We have such terrible treatments right now for the neuropathy of diabetes," said corresponding author Amy Paller, MD, the Walter J. Hamlin professor of dermatology at Northwestern University Feinberg School of Medicine and director of Northwestern's Skin Disease Research Center in Chicago. "We're basically only treating the pain. This is a novel pathogenesis-based approach that looks at what's causing the neuropathy and reverses that instead of just treating the pain."

After finding that by depleting GM3 through genetic modification prevented the development of neuropathy in mice, the researchers created an ointment to reduce the chemical and the enzyme that makes it.

The scientists compared the appearance and function of the mice’s nerves when they were exposed to ointment to when they weren’t. They tested their pain responses and found that when exposed to the ointment, their pain reactions were no different from mice that had low levels of GM3.

Going forward, the researchers want to further test the ointment on humans in clinical trials to conclude it has the same beneficial effect.

"If the studies look promising in mice, our long-term goal would be to further test safety and advance to human clinical trials to prevent and/or reverse the development of diabetic neuropathy," Paller said.

http://www.cardiovascularbusiness.com/topics/practice-management/quality/researchers-develop-ointment-reverse-neuropathy-diabetic-patients

The Role Of The FDA In Testing New Drugs

Today's post from healthychildren.org (see link below) is especially interesting to neuropathy patients who are not only confronted by a long list of drugs intended for other medical purposes but are also tempted by claims elsewhere, of miraculous cures and treatments involving strangely-named medications. Most people have heard of the FDA (The U.S. Food and Drug Administration) and are aware that that body approves and disapproves new medications as they come on the market. For people outside the USA, their own health authorities very often follow the guidelines of the FDA when it comes to making drugs available in their own lands. It's useful then to know how the FDA works and how and why it comes to its conclusions. Remember, the FDA almost always errs on the side of caution, so you can be reasonably sure that if a drug is FDA approved, it's safe. There have been slip-ups in the past but these are generally swiftly rectified. Interesting article.

FDA’s Role in the Drug Approval Process

Last Updated4/2/2015 SourceAmerican Academy of Pediatrics and U.S. Food and Drug Administration (Copyright © 2015)
This article provides information about the FDA's drug approval process.

What Does it Mean For a Product to be "FDA-Approved?"

The U.S. Food and Drug Administration (FDA) examines, tests, and approves a wide range of items for medical use, including drugs, medical devices, food, cosmetics and many other health-related products. In the simplest terms, "FDA approval" means that the FDA has decided the benefits of the approved item outweigh its potential risks.

Before the FDA, companies could make claims about a product, without proof that it was safe or that it even worked. This made consumers extremely vulnerable. Now, new products must go through the FDA approval process before they are available to the public.

Why is the FDA Approval Process Important?

FDA approval is important, because it validates the need for research on how drugs work on children, not just adults. It also allows us the properly determine the appropriate dosage for children, determine the best route of administration, and test for any drug interactions.

How Does a Drug or Device Get FDA Approval?

In order to receive FDA approval for a drug or a medical device, the manufacturer must prove to the FDA that the item is "safe and effective." Although no drug or medical device is entirely risk-free, the research and testing must show that the benefits of the drug or device for a particular condition outweigh the risks to patients of using the item.
Here's a brief overview of the steps involved in a drug becoming FDA-approved:
Drug Developed: A company develops a new drug and seeks to have it approved by the FDA for sale in the United States.

Animal Testing: Before testing the drug on people, the company must test the new drug on animals to find out whether it has the potential to cause serious harm (i.e. toxicity).
IND Application: The company submits an Investigational New Drug (IND) application to the FDA based on the results from the initial animal testing. These results must include the drug's composition and manufacturing and the proposed plan for testing the drug on people.
Clinical Trials: After the FDA reviews and approves the IND application, clinical trials to test the drug on people can begin. There are 4 phases of clinical trials, starting with small-scale trials, followed by large-scale trials. After the clinical trials, the researchers then submit study reports to the FDA.
NDA Application: Once a drug developer provides evidence that the drug is safe and effective, the company can file a New Drug Application (NDA). The FDA reviews the application and makes a decision to approve or not approve the drug.
Drug Labeling: The FDA reviews the drug's labeling/packaging and makes sure appropriate information is communicated to health care professionals and consumers.
Facility Inspection: The FDA inspects the facilities where the drug will be manufactured.
Drug Approval: The FDA approves the NDA or issues a response letter.
Post-Marketing Monitoring: Once the FDA approves the drug, the company is required to submit periodic safety updates to the FDA. 

Do Over-the-Counter Drugs and Medical Devices Need FDA Approval?

Yes. Drugs sold over-the-counter (without a prescription) must be approved by the FDA. For instance, over-the-counter pain medications must be FDA-approved to treat pain.

What is Considered When Rescheduling A Drug?

The Controlled Substances Act (CSA), part of the Comprehensive Drug Abuse Prevention and Control Act of 1970, is the legal cornerstone of the government’s war against drug abuse. The U.S. Drug Enforcement Administration (DEA) has divided these substances into five categories, called “schedules,” based on each drug’s (1) potential for abuse, (2) safety, (3) addictive potential and (4) whether or not it has any legitimate medical applications.. Schedule I is reserved for drugs considered to have the highest potential for abuse and no current accepted medical use. Rescheduling marijuana, for example, would not make it legal but reclassifying the schedule could potentially increase research being done on the drug. Click here to learn more about the FDA's drug approval approcess and marijuana.

http://www.healthychildren.org/English/health-issues/conditions/treatments/Pages/FDAs-Role-in-the-Drug-Approval-Process.aspx

SEE THROUGH SENSORS OPEN NEW WINDOW IN TO THE BRAIN

Developing invisible implantable medical sensor arrays, a team of University of Wisconsin-Madison engineers has overcome a major technological hurdle in researchers' efforts to understand the brain.

The team described its technology, which has applications in fields ranging from neuroscience to cardiac care and even contact lenses, in the Oct. 20 issue of the online journal Nature Communications.

Neural researchers study, monitor or stimulate the brain using imaging techniques in conjunction with implantable sensors that allow them to continuously capture and associate fleeting brain signals with the brain activity they can see. However, it's difficult to see brain activity when there are sensors blocking the view.

"One of the holy grails of neural implant technology is that we'd really like to have an implant device that doesn't interfere with any of the traditional imaging diagnostics," says Justin Williams, a professor of biomedical engineering and neurological surgery at UW-Madison. "A traditional implant looks like a square of dots, and you can't see anything under it. We wanted to make a transparent electronic device."

The researchers chose graphene, a material gaining wider use in everything from solar cells to electronics, because of its versatility and biocompatibility. And in fact, they can make their sensors incredibly flexible and transparent because the electronic circuit elements are only 4 atoms thick -- an astounding thinness made possible by graphene's excellent conductive properties. "It's got to be very thin and robust to survive in the body," says Zhenqiang (Jack) Ma, a professor of electrical and computer engineering at UW-Madison. "It is soft and flexible, and a good tradeoff between transparency, strength and conductivity."

Drawing on his expertise in developing revolutionary flexible electronics, he, Williams and their students designed and fabricated the microelectrode arrays, which -- unlike existing devices -- work in tandem with a range of imaging technologies. "Other implantable microdevices might be transparent at one wavelength, but not at others, or they lose their properties," says Ma. "Our devices are transparent across a large spectrum -- all the way from ultraviolet to deep infrared. We've even implanted them and you cannot find them in an MR scan."

The transparent sensors could be a boon to neuromodulation therapies, which physicians increasingly are using to control symptoms, restore function, and relieve pain in patients with diseases or disorders such as hypertension, epilepsy, Parkinson's disease, or others, says Kip Ludwig, a program director for the National Institutes of Health neural engineering research efforts. "Despite remarkable improvements seen in neuromodulation clinical trials for such diseases, our understanding of how these therapies work -- and therefore our ability to improve existing or identify new therapies -- is rudimentary."

Currently, he says, researchers are limited in their ability to directly observe how the body generates electrical signals, as well as how it reacts to externally generated electrical signals. "Clear electrodes in combination with recent technological advances in optogenetics and optical voltage probes will enable researchers to isolate those biological mechanisms. This fundamental knowledge could be catalytic in dramatically improving existing neuromodulation therapies and identifying new therapies."

The advance aligns with bold goals set forth in President Barack Obama's BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative. Obama announced the initiative in April 2013 as an effort to spur innovations that can revolutionize understanding of the brain and unlock ways to prevent, treat or cure such disorders as Alzheimer's and Parkinson's disease, post-traumatic stress disorder, epilepsy, traumatic brain injury, and others.

While the team centered its efforts on neural research, they already have started to explore other medical device applications. For example, working with researchers at the University of Illinois-Chicago, they prototyped a contact lens instrumented with dozens of invisible sensors to detect injury to the retina; the UIC team is exploring applications such as early diagnosis of glaucoma.

Additional authors on the Nature Communications paper include UW-Madison electrical and computer engineering graduate students Dong-Wook Park and Solomon Mikael, materials science graduate student Amelia A. Schendel, biomedical engineering research specialist Sarah K. Brodnick; biomedical engineering graduate students Thomas J. Richner, Jared P. Ness and Mohammed R. Hayat; collaborators Farid Atry, Seth T. Frye and Ramin Pashaie of the University of Wisconsin-Milwaukee; and Sanitta Thongpang of Mahidol University in Bangkok, Thailand.

The researchers are patenting their technology through the Wisconsin Alumni Research Foundation. Funding for the research came from the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, and the U.S. Office of Naval Research.

Tapentadol A New Alternative For Neuropathic Pain

Today's post comes from marketwatch.com (see link below) and is a press release for Tapentadol, a new centrally-acting opioid made by Janssen Pharmceuticals to control neuropathic pain. Far be it from me to promote either a company or an opioid but we're always looking for alternatives to the treatments that either don't work, or have unpleasant side effects. This is another opium derivative, so there will undoubtedly be issues regarding side effects and addiction for some people but the tests look promising. The post is long because Janssen have provided a complete description of how the drug works and what the potential side effects may be and that's worth reading. One assumes that this information will all appear on the leaflet inside the box when the drug achieves general release. Tapentadol will not be for everybody, as is the case for all similar treatments but it may be a breakthrough for some. Time will tell.
More information about Tapentadol can be found here (and is easier to digest),

Phase 3 Data Show NUCYNTA® ER (tapentadol) Extended-Release Tablets Provide Pain Management for Patients with Diabetic Peripheral Neuropathy (DPN)

Study results presented at the 31st Annual Scientific Meeting of the American Pain Society

press release May 17, 2012,

RARITAN, N.J., May 17, 2012 /PRNewswire via COMTEX/ -- Janssen Pharmaceuticals, Inc. today announced the results of an investigational Phase 3 study suggesting NUCYNTA® ER (tapentadol) extended-release tablets were significantly more effective than placebo in providing pain management among adults with chronic moderate to severe, painful diabetic peripheral neuropathy (DPN). Results of the study were presented at the 31st Annual Scientific Meeting of the American Pain Society being held May 16-19 in Honolulu, Hawaii.

Diabetes affects nearly 26 million people in the United States(1)- and its prevalence is expected to grow significantly during the coming decades(2). Over time, people with diabetes can develop a type of nerve damage called neuropathy. Approximately 60 to 70 percent of people with diabetes have some form of neuropathy(3). The most common type is diabetic peripheral neuropathy, which causes pain or loss of feeling in the toes, feet, legs, hands, and arms.

The study found, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with tapentadol ER, those who continued on an optimized dose of tapentadol ER (100-250 mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo(4). Treatment-emergent adverse events reported in 10 percent or more of tapentadol ER-treated patients during the double-blind maintenance period included nausea (21.1 percent) and vomiting (12.7 percent)(4).

"Painful DPN is a common and burdensome complication of diabetes, and controlling pain in people with DPN can be challenging," said Aaron I. Vinik, M.D., Ph.D., FCP, MACP, Director of Research and Neuroendocrine Unit at Strelitz Diabetes Center for Endocrine and Metabolic Disorders at Eastern Virginia Medical School, and lead investigator of the study. "These data suggest tapentadol ER provides a significant reduction in chronic pain in adult patients with DPN."

The findings of this study are consistent with those of another Janssen-sponsored study published early last year, which found tapentadol ER to be effective versus placebo for relieving moderate to severe chronic pain associated with diabetic peripheral neuropathy.

"We are pleased the Phase 3 data presented today showed tapentadol ER was effective at providing pain management for patients with chronic, moderate to severe pain associated with DPN," said Christine Rauschkolb, M.D., Ph.D., Vice President and Head of Integrated Operations, Janssen Research & Development, LLC and one of the study's authors. "Janssen has a long history of helping physicians provide responsible treatment for patients to relieve their acute and chronic pain. We are committed to developing new pain management options for the millions of Americans who have painful DPN."

About the Study

This Phase 3 clinical trial was a randomized-withdrawal, placebo-controlled study. It enrolled adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. This trial had three phases: an open-label phase, which included a 3-week titration period during which the individually optimized tapentadol ER dose (100-250 mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking tapentadol ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10 to 14 days after discontinuation of study drug.

The primary efficacy endpoint of the study was the mean change in average pain intensity from baseline (point of randomization) to the last week of the 12-week, double-blind maintenance phase, as determined by an 11-point pain rating scale or numerical rating scale (NRS; 0='no pain,' 10='pain as bad as you can imagine'). Safety assessments were performed on the open-label and double-blind safety populations (all patients who received greater than or equal to 1 dose of open-label and double-blind treatment, respectively). Treatment-emergent adverse events (TEAEs), defined as any AEs (new or worse in intensity) that occurred after the first intake of study drug during the open-label or double-blind phase, were monitored throughout the study.

In the open-label titration period, 459 patients received one or more doses of tapentadol ER and were included in the open-label safety population. At the start of the 3-week, open-label phase, the majority of patients (87.1 percent) reported severe pain (6 or more on the 11-point NRS) with a mean pain intensity of 7.3. By the end of the open-label phase, the mean pain intensity was reduced to 3.6. Treatment-emergent adverse events (TEAEs) experienced by 10 percent or more of patients during the open-label phase were nausea (24.4 percent), dizziness (17), constipation (11.8) and somnolence (10.7).

A total of 358 patients completed the open-label titration period; 318 were randomized and received one or more dose of study medication (n=152 for placebo, 166 for tapentadol ER).

Following randomization, during the double-blind treatment phase to week 12, pain increased in the placebo group (as demonstrated by the mean change in pain intensity of 1.3), while in the tapentadol ER group, efficacy was maintained, as indicated by the mean change in pain intensity of 0.28. The least-squares mean difference between the tapentadol ER and placebo groups in the change in average pain intensity was -0.95 on the 11-point NRS favoring tapentadol ER (95 percent CI, -1.42 to -0.49; p<0.001, tapentadol ER vs. placebo)(4).

For more details about the study design, please visit www.clinicaltrials.gov (NCT01041859).

Janssen Research & Development, LLC and Grunenthal GmbH, conducted this study, which Janssen Research & Development, LLC has included as part of its Supplemental New Drug Application (sNDA) submitted on October 28, 2011 to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of neuropathic pain associated with DPN in patients 18 years of age or older. The FDA currently is reviewing this supplemental application.

About Tapentadol and NUCYNTA® ER

Tapentadol is a centrally-acting synthetic analgesic. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA® ER (tapentadol) extended-release tablets are an oral analgesic available by prescription only and indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. NUCYNTA® ER is taken twice daily and available in 50 mg, 100 mg, 150 mg, 200 mg and 250 mg strengths.

Outside the United States, tapentadol is marketed by Janssen Inc. in Canada; Grünenthal GmbH discovered tapentadol and markets immediate- and extended-release formulations of tapentadol (PALEXIA®) in various countries in Europe.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA® ER (tapentadol) extended-release tablets

WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTION, AND LIMITATIONS OF USE

Potential for Abuse

NUCYNTA® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances, which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection

NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use

NUCYNTA® ER is not intended for use as an as-needed analgesic.

NUCYNTA® ER is not intended for the management of acute or postoperative pain.

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.

Patients must not consume alcoholic beverages, or prescription or nonprescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA® ER may result in a potentially fatal overdose of tapentadol.

CONTRADICTIONS

NUCYNTA® ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.

NUCYNTA® ER is contraindicated in any patient who has or is suspected of having a paralytic ileus.

NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

NUCYNTA® ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.

WARNINGS & PRECAUTIONS

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, crushed, or dissolved NUCYNTA® ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.

NUCYNTA® ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTA® ER, especially in children, can result in a fatal overdose of tapentadol.

Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.

Use NUCYNTA® ER with caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve, such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA® ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered, and NUCYNTA® ER should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.

Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® ER may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma, or death may result if these drugs are taken in combination with NUCYNTA® ER. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.

Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA® ER should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure, such as those with evidence of head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. NUCYNTA® ER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carries the risk of addiction even under appropriate medical use.

Drug abusers may attempt to abuse NUCYNTA® ER by crushing, chewing, snorting, or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA® ER and pose a significant risk to the abuser that could result in overdose and death.

NUCYNTA® ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (eg, phenothiazines, general anesthetics).

Patients should be cautioned that NUCYNTA® ER may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This is to be expected, especially at the beginning of treatment, at any change of dosage, as well as in combination with alcohol or tranquilizers.

NUCYNTA® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma, or death may result.

NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA® ER should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.

Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.

Withdrawal symptoms may occur if NUCYNTA® ER is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA® ER.

A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.

NUCYNTA® ER has not been studied in patients with severe hepatic impairment, and use in this population is not recommended.

Like other drugs with mu-opioid agonist activity, NUCYNTA® ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

NUCYNTA® ER should be used with caution in the following conditions: adrenocortical insufficiency (eg, Addison's disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis.

Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA® ER in pregnant women. NUCYNTA® ER should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus.

ADVERSE REACTIONS

The most common (greater than equal to 10%) adverse reactions were nausea, constipation, headache, dizziness, and somnolence.

About Janssen Pharmaceuticals, Inc. and Janssen Research and Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop and bring innovative products, services and solutions to people throughout the world.

Janssen Pharmaceuticals, Inc., and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies.

Janssen Pharmaceuticals, Inc. provides medicines for an array of health concerns in several therapeutic areas. Innovative therapies Janssen Pharmaceuticals, Inc. offers currently include ACIPHEX® (rabeprazole sodium), DORIBAX® (doripenem for injection), ELMIRON® (pentosan polysulfate sodium), NUCYNTA® (tapentadol), NUCYNTA® ER (tapentadol) extended-release tablets and XARELTO® (rivaroxaban) tablets. The full prescribing information for NUCYNTA® ER, including boxed warnings, is available here; the full prescribing information for XARELTO®, including boxed warnings, is available here.

For more information on Janssen Pharmaceuticals, Inc., visit us at www.janssenpharmaceuticalsinc.com or follow us on Twitter at www.twitter.com/JanssenUS .

For more information on Janssen Research & Development, LLC, visit us at http://www.janssenrnd.com/ .

http://www.marketwatch.com/story/phase-3-data-show-nucynta-er-tapentadol-extended-release-tablets-provide-pain-management-for-patients-with-diabetic-peripheral-neuropathy-dpn-2012-05-17

A New Alternative To Opiates For Nerve Pain

Today's post from consultqd.clevelandclinic.org (see link below) talks about a new advance in stem cell therapy concerning mesenchymal stem cells (MSC). These have been shown to reduce nerve pain and if they are injected directly into the vein, they have also been shown to reduce the side effects and addictiveness of opioids. Of course it's not as simple as this but these wonder cells apparently also can travel to the site of nerve injury and repair nerve cells on the spot. It may all seem a bit sci-fi and magical but it is true and reveals the huge potential of stem-cell therapy for all sorts of medical issues in the future. The fact that mesenchymal stem cells (MSC) directly apply to neuropathy problems makes it an exciting development for nerve pain patients across the world. Now we have to find the money in state budgets to develop the science and insurance companies who will pay for the treatment - don't hold your breath.

 Stem Cell Therapy for Neuropathic Pain: New Findings Show Promise
Animal studies demonstrate effectiveness

Aug. 10, 2016 / Pain Management / Research

Stem cell research at Cleveland Clinic could pave the way for an entirely new approach to chronic pain treatment that reduces medicine’s current reliance on opioid therapy for intractable pain. The modality also shows promise as a tool to reverse opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), particularly problematic side effects of opioid therapy. Jianguo Cheng, MD, PhD, and his colleagues at Cleveland Clinic have developed patented methods of attenuating opioid tolerance.

Animal studies by Dr. Cheng and his colleagues have demonstrated the effectiveness of mesenchymal stem cell (MSC) transplantation in reducing hyperalgesia due to nerve injury. The group’s work has shown MSC transplantation’s effectiveness in reducing pain induced by sciatic nerve injury in rats and mice. MSC transplantation significantly reduced pain sensitivity evaluated by foot withdrawal thresholds in animals in response to thermal or mechanical stimulation. These cells produced immune modulatory and anti-inflammatory effects, promoted sensory nerve repair, and showed strong analgesic properties that could provide a safer and more effective alternative to current treatment modalities, in the management of neuropathic pain, says Dr. Cheng, Professor of Anesthesiology and Director of the Cleveland Clinic Multidisciplinary Pain Medicine Fellowship Program.

Pain medicine researchers are searching for an alternative to opioid therapy because neuropathic pain often does not respond to morphine and other opioids. Opioid analgesics can also lead to a variety of complications, ranging from itching and constipation to dependence, addiction, respiratory depression and death.

About 30 percent of neuropathy cases are caused by nerve damage associated with diabetes. However, hundreds of diseases are linked to neuropathic pain. Sources of neuropathic pain include alcoholism, amputation (which can result in phantom pain), some chemotherapy drugs (for example, Cisplatin®, Paclitaxel®, Vincristine®), radiation therapy, complex regional pain syndrome type II, trigeminal neuralgia, shingles, spinal stenosis, and central nervous system disorders, such as Parkinson disease and multiple sclerosis.

Recent research by Dr. Cheng and his group has yielded new discoveries that bode well for MSC transplantation as a potential future treatment modality. One investigation compared the analgesic effects of MSC derived from bone marrow with MSC derived from adipose tissue. Adipose-derived cells were found to be as efficacious as bone marrow-derived cells in reducing neuropathic pain in rats. The finding suggests that stem cell therapy could offer a practical option because stem cells from adipose tissue are relatively easy to obtain.

Recent investigations by Dr. Cheng and his colleagues comparing the analgesic effectiveness of intrathecal versus intravenous methods of MSC transplantation show both methods to be equally effective. The finding has important implications because intravenous transplantation of MSC could offer a safer and more expeditious route of delivery than intrathecal transplantation.

“We originally thought that stem cells would have to be introduced intrathecally in order to reduce pain, and that stem cells introduced intravenously would pass through the lungs and fail to produce analgesia,” says Dr. Cheng. “The finding that intravenous transplantation is as effective as intrathecal transplantation is encouraging.”

Dr. Cheng’s group has also discovered that MSCs can be found in the area surrounding the injured nerve following MSC transplantation. “For reasons we do not yet fully understand, these cells have the ability to migrate to the injury site to promote repair of the injured nerve fibers,” Dr. Cheng says. “The cells can sense the injury’s location and travel to it.”

Although many questions must be answered before it can be known whether stem cell therapy is safe and effective for humans, some small patient studies show potential, Dr. Cheng says. According to one observational study in Australia, MSC transplantation reduced pain in patients suffering from trigeminal neuralgia, a particularly difficult condition to treat. “Though the findings are preliminary, the study provides some evidence that what we have learned in the laboratory can be translated to clinical use,” Dr. Cheng says.

Dr. Cheng’s team has achieved analgesia with MSC transplantation from rats to mice, providing early evidence that stem cells’ anti-inflammatory and immuno-modulatory properties can be transferred between species. An important pre-clinical study will be to see whether the transplantation of human stem cells to animals also can produce analgesic and anti-tolerance effects, Dr. Cheng says.

Dr. Cheng’s team presented research at the 2016 annual meeting of the American Academy of Pain Medicine showing MSC’s potential to reverse opioid tolerance and opioid-induced hyperalgesia, problems that can compromise the safety and efficacy of opioid therapy. Intravenous transplantation of bone marrow-derived MSC significantly attenuated OT and OIH in animals whether the transplantation was performed seven days before or 14 days after the initiation of daily morphine injections. These data demonstrate that MSC transplantation can not only prevent the development of OT and OIH but can also reverse it.

https://consultqd.clevelandclinic.org/2016/08/stem-cell-therapy-neuropathic-pain-new-findings-show-promise/

New And Exciting Stem Cell Therapy For Neuropathy

Today's post from painnewsnetwork.org (see link below) is another article proclaiming the latest 'breakthrough' in neuropathy treatment. Don't worry, it's not a lurid advertisement from yet another questionable neuropathy clinic but shows the results of new research on stem-cell therapy. If you read it, you may justifiably get excited at the prospect of a pain-free existence thanks to bone marrow cell injections but this sort of treatment on humans is a long way off and as such can be frustrating information for many neuropathy patients. Nevertheless, the field of stem-cell therapy is beginning to show multiple promising results and as such makes interesting reading and gives hope for the future.

‘Amazing’ New Stem Cell Treatment for Neuropathy
By Pat Anson, Editor July 13, 2015

Researchers at Duke University say an experimental stem cell therapy being tested on animals shows great potential to provide long-lasting pain relief for people suffering from diabetic neuropathy or other types of nerve damage.

In a study published in the Journal of Clinical Investigation, researchers said mice injected with a type of stem cell known as bone marrow stromal cells (BMSCs) were much less sensitive to nerve pain.

"This analgesic effect was amazing," said Ru-Rong Ji, PhD, a professor of anesthesiology and neurobiology in the Duke School of Medicine. "Normally, if you give an analgesic, you see pain relief for a few hours, at most a few days. But with bone marrow stem cells, after a single injection we saw pain relief over four to five weeks."

BMSCs are known to produce an array of healing factors and can be coaxed into forming other types of cells in the body. They are already being used to treat people with serious burns, inflammatory bowel disease, heart damage and stroke.

"Based on these new results, we have the know-how and we can further engineer and improve the cells to maximize their beneficial effects," said Ji.

Researchers injected the mice with stem cells through a lumbar puncture, infusing them into the fluid that bathes the spinal cord.

The picture on the right shows how the injected stem cells (in red) migrated to the site of the nerve injury and were still present four weeks after treatment.

A molecule emitted from the injured nerve cells -- which has previously been linked to neuropathic pain – is believed to act as a “homing signal” and attract the stem cells.

Researchers measured levels of anti-inflammatory molecules in the mice and found that one in particular, TGF-β1, was present in higher amounts in the spinal fluid of the stem cell-treated animals.

TGF-β1 is a protein that is secreted by immune cells and is common throughout the body. Research has shown that people with chronic pain have too little TGF-β1.

Injecting TGF-β1 directly into spinal cord fluid provides pain relief, but only for a few hours, according to Ji. By contrast, bone marrow stromal cells stay on site for as much as three months after the infusion.

Ji’s research team is working to identify stem cells that produce more TGF-β1, as well as other types of pain relieving molecules. In addition to diabetic neuropathy, researchers believe stem cell therapy could also be used to treat pain from chemotherapy, surgical amputation, lower back pain and spinal cord injuries.

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association. Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can lead to injuries, chronic foot ulcers and even amputations.

Another recent animal study by researchers in the U.S. and South Korea found that diabetic rats given intramuscular injections of bone marrow stromal cells experienced both angiogenesis (blood vessel growth) and a restoration of the myelin sheath -- a protective covering over nerve cells damaged by neuropathy.

"Currently, the only treatment options available for DN (diabetic neuropathy) are palliative in nature, or are directed at slowing the progression of the disease by tightly controlling blood sugar levels," said Dr. John Sladek, Jr., Professor of Neurology, Pediatrics, and Neuroscience, Department of Neurology at the University of Colorado School of Medicine.

"This study offers new insight into the benefits of cell therapy as a possible treatment option for a disease that significantly diminishes quality of life for diabetic patients.”

The study is being published in the journal Cell Transplantation.

http://www.painnewsnetwork.org/stories/2015/7/12/amazing-stem-cell-treatment-for-neuropathy

NEW TECHNOLOGY MAKINGS TISSUES SOMEDAY MAY ORGANS

A new instrument could someday build replacement human organs the way electronics are assembled today: with precise picking and placing of parts.

In this case, the parts are not resistors and capacitors, but 3-D microtissues containing thousands to millions of living cells that need a constant stream of fluid to bring them nutrients and to remove waste. The new device is called 'BioP3' for pick, place, and perfuse. A team of researchers led by Jeffrey Morgan, a Brown University bioengineer, and Dr. Andrew Blakely, a surgery fellow at Rhode Island Hospital and the Warren Alpert Medical School, introduces BioP3 in a new paper in the journal Tissue Engineering Part C.

Because it allows assembly of larger structures from small living microtissue components, Morgan said, future versions of BioP3 may finally make possible the manufacture of whole organs such as livers, pancreases, or kidneys.

"For us it's exciting because it's a new approach to building tissues, potentially organs, layer by layer with large, complex living parts," said Morgan, professor of molecular pharmacology, physiology and bBiotechnology. "In contrast to 3-D bioprinting that prints one small drop at a time, our approach is much faster because it uses pre-assembled living building parts with functional shapes and a thousand times more cells per part."

Morgan's research has long focused on making individual microtissues in various shapes such as spheres, long rods, donut rings and honeycomb slabs. He uses a novel micromolding technique to direct the cells to self-assemble and form these complex shapes. He is a founder of the Providence startup company MicroTissues Inc., which sells such culture-making technology.

Now, the new paper shows, there is a device to build even bigger tissues by combining those living components.

"This project was particularly interesting to me since it is a novel approach to large-scale tissue engineering that hasn't been previously described," Blakely said.

The BioP3 prototype

The BioP3, made mostly from parts available at Home Depot for less than $200, seems at first glance to be a small, clear plastic box with two chambers: one side for storing the living building parts and one side where a larger structure can be built with them. It's what rests just above the box that really matters: a nozzle connected to some tubes and a microscope-like stage that allows an operator using knobs to precisely move it up, down, left, right, out and in.

The plumbing in those tubes allows a peristaltic pump to create fluid suction through the nozzle's finely perforated membrane. That suction allows the nozzle to pick up, carry and release the living microtissues without doing any damage to them, as shown in the paper.

Once a living component has been picked, the operator can then move the head from the picking side to the placing side to deposit it precisely. In the paper, the team shows several different structures Blakely made including a stack of 16 donut rings and a stack of four honeycombs. Because these are living components, the stacked microtissues naturally fuse with each other to form a cohesive whole after a short time.

Because each honeycomb slab had about 250,000 cells, the stack of four achieved a proof-of-concept, million-cell structure more than 2 millimeters thick.

That's not nearly enough cells to make an organ such as a liver (an adult's has about 100 billion cells), Morgan said, but the stack did have a density of cells consistent with that of human organs. In 2011, Morgan's lab reported that it could make honeycomb slabs 2 centimeters wide, with 6 million cells each. Complex stacks with many more cells are certainly attainable, Morgan said.

If properly nurtured, stacks of these larger structures could hypothetically continue to grow, Morgan said. That's why the BioP3 keeps a steady flow of nutrient fluid through the holes of the honeycomb slabs to perfuse nutrients and remove waste. So far, the researchers have shown that stacks survive for days.

In the paper the team made structures with a variety of cell types including H35 liver cells, KGN ovarian cells, and even MCF-7 breast cancer cells (building large tumors could have applications for testing of chemotherapeutic drugs or radiation treatments). Different cell types can also be combined in the microtissue building parts. In 2010, for example, Morgan collaborated on the creation of an artificial human ovary unifying three cell types into a single tissue.

Improvements underway

Because version 1.0 of the BioP3 is manually operated, it took Blakely about 60 minutes to stack the 16 donut rings around a thin post, but he and Morgan have no intention of keeping it that way.

In September, Morgan received a $1.4-million, three-year grant from the National Science Foundation in part to make major improvements, including automating the movement of the nozzle to speed up production.

"Since we now have the NSF grant, the Bio-P3 will be able to be automated and updated into a complete, independent system to precisely assemble large-scale, high-density tissues," Blakely said.

In addition, the grant will fund more research into living building parts -- how large they can be made and how they will behave in the device over longer periods of time. Those studies include how their shape will evolve and how they function as a stack.

"We are just at the beginning of understanding what kinds of living parts we can make and how they can be used to design vascular networks within the structures," Morgan said. "Building an organ is a grand challenge of biomedical engineering. This is a significant step in that direction."

Brown has sought a patent on the BioP3.

In addition to Blakely and Morgan, the paper's other authors are biology graduate student Kali Manning and Anubhav Tripathi, profesor of engineering, who co-directs Brown's Center for Biomedical Engineering with Morgan.

The National Institutes of Health (grant T32 GM065085-09) and the NSF (grant CBET-1428092) have supported the research.