NEW ANTIBIOTIC ATTACK S DRUG RESISTANT MICROBES

The multitude of microbes scientists have found populating the human body have good, bad and mostly mysterious implications for our health. But when something goes wrong, we defend ourselves with the undiscriminating brute force of traditional antibiotics, which wipe out everything at once, regardless of the consequences.

Researchers at Rockefeller University and their collaborators are working on a smarter antibiotic. And in research to be published October 5 in Nature Biotechnology, the team describes a 'programmable' antibiotic technique that selectively targets the bad bugs, particularly those harboring antibiotic resistance genes, while leaving other, more innocent microbes alone.

"In experiments, we succeeded in instructing a bacterial enzyme, known as Cas9, to target a particular DNA sequence and cut it up," says lead researcher Luciano Marraffini, head of the Laboratory of Bacteriology. "This selective approach leaves the healthy microbial community intact, and our experiments suggest that by doing so you can keep resistance in check and so prevent certain types of secondary infections, eliminating two serious hazards associated with treatment by classical antibiotics."

The new approach could, for instance, reduce the risk of C. diff, a severe infection of the colon, caused by the Clostridium difficile bacterium, that is associated with prolonged courses of harsh antibiotics and is a growing public health concern.

The Cas9 enzyme is part of a defense system that bacteria use to protect themselves against viruses. The team coopted this bacterial version of an immune system, known as a CRISPR (clustered regularly interspaced short palindromic repeats) system and turned it against some of the microbes. CRISPR systems contain unique genetic sequences called spacers that correspond to sequences in viruses. CRISPR-associated enzymes, including Cas9, use these spacer sequences as guides to identify and destroy viral invaders.

The researchers were able to direct Cas9 at targets of their choosing by engineering spacer sequences to match bacterial genes then inserting these sequences into a cell along with the Cas9 gene. The cell's own machinery then turns on the system. Depending on the location of the target in a bacterial cell, Cas9 may kill the cell or it may eradicate the target gene. In some cases, a treatment may prevent a cell from acquiring resistance, they found.

"We previously showed that if Cas9 is programmed with a target from a bacterial genome, it will kill the bacteria. Building on that work, we selected guide sequences that enabled us to selectively kill a particular strain of microbe from within a mixed population," says first author David Bikard, a former Rockefeller postdoc who is now at the Pasteur Institute in Paris.

In initial experiments, Bikard and colleagues targeted a strain of the common skin and respiratory bacteria Staphylococcus aureus that is resistant to the antibiotic kanamycin. Treatment by Cas9 programmed to target a part of the resistance gene killed most of the resistant Staph, but left behind the kanamycin-susceptible Staph.

Targeted bacterial genocide is only one option. Bacteria share genes, including those conferring drug resistance, in the form of rings of DNA known as plasmids. In a second series of experiments, researchers turned Cas9 on tetracycline resistance-harboring plasmids in a strain of the potentially deadly multidrug resistant bacteriaStaphylococcus aureus (MRSA). Not only did the resistant cells become sensitive to tetracycline after Cas9 destroyed the plasmids, but the arrival of Cas9 in other Staphcells acted as an immunization, preventing them from taking on resistance-carrying plasmids.

And, in a final set of experiments, conducted in collaboration with Vincent Fischetti's Laboratory of Bacterial Pathogenesis and Immunology, adjunct faculty member Chad Euler confirmed their test tube results on living skin, by using Cas9 to selectively kill kanamycin-resistant Staph infecting the shaved backs of mice.

In spite of the promising results, the delivery system needs improvement. The researchers used bacteria-infecting viruses to inject the programmed Cas9 enzymes into the bacterial cells, but these viruses only attack specific types of cells. Scientists need to devise a less discriminating method of delivery, before the technology can be used to develop a new class of antibiotics, Marraffini says.

In addition to its potential as a much-needed new weapon against drug-resistant microbes, the new system could also be used to advance research on the complex populations of microbes in the body, about which very little is known. "There are enormous microbial communities in the human body," Marraffini says. "Programmable Cas9 enzymes may make it possible to analyze these populations by eliminating their members, one by one, and studying the effects."

New Drug Development May End Up Replacing Morphine

Today's post from sciencedaily.com (see link below) is an interesting new development in finding effective ways to block pain signals for people like neuropathy and cancer sufferers. New research has discovered new compounds which bind to specific molecules (opioid receptors) on nerve cells. Opioids do this already but we all know the dangers of opioids and addiction and the need for ever increasing dosages. These new compounds attach themselves to a different part of the nerve cell but work in the same way without the normal opioid side effects. That's the theory anyway and as with many of these promising developments, sometimes you wish they wouldn't tell us about them until they're almost in production. Getting patients' hopes up but then letting them wait for years can be demoralising in itself. However, it does sound very promising and this is an easy to read article even though it's looking at the science at a molecular level.

A Path to Lower-Risk Painkillers: Newly-Discovered Drug Target Paves Way for Alternatives to Morphine
This story is reprinted from materials provided by University of Michigan Health System June 10, 2013

 For patients managing cancer and other chronic health issues, painkillers such as morphine and Vicodin are often essential for pain relief. The body's natural tendency to develop tolerance to these medications, however, often requires patients to take higher doses -- increasing risks of harmful side effects and dependency.

Now, new research from the University of Michigan Health System and a major pharmaceutical company has identified a novel approach to moderate and severe pain therapy that paves the way for lower dosage painkillers. The findings appear in Proceedings of the National Academy of Sciences.

Drugs such as hydrocodone (the main ingredient of Vicodin) and oxycodone (Oxycontin) are often the best options for the treatment of moderate to severe pain for patients facing medical conditions ranging from a wisdom tooth extraction to cancer. The drugs bind to specific molecules (opioid receptors) on nerve cells in the brain and spinal cord to prevent the feeling of pain.

"We have for the first time discovered compounds that bind to an alternative site on the nerve opioid receptors and that have significant potential to enhance the drug's positive impact without increasing negative side effects," says co-author John Traynor, Ph.D., professor of pharmacology at the U-M Medical School.

"We are still in the very early stages of this research with a long way to go, but we believe identifying these compounds is a key step in revolutionizing the treatment of pain. This opens the door to developing pain relief medications that require lower doses to be effective, helping address the serious issues of tolerance and dependence that we see with conventional pain therapy."

Conventional drug treatments for pain work by targeting the so-called orthosteric site of the opioid receptor that provides pain relief. Targeting this site, however, is a double-edged sword because it is also responsible for all of the drug's unwanted side effects, such as constipation and respiratory depression. Tolerance also limits chronic use of the drugs because higher doses are required to maintain the same effect.

Using cell systems and mouse brain membranes, researchers have identified compounds that bind to a physically distinct and previously unknown "allosteric" site on the opioid receptor- a site that fine-tunes the activity of the receptor. Not only do these compounds act at a location that hasn't been studied as a drug target before but they bind to the receptor in a new way to enhance the actions of morphine -- which means lower doses can have the same impact.

"The newly-discovered compounds bind to the same receptor as morphine but appear to act at a separate novel site on the receptor and therefore can produce different effects. What's particularly exciting is that these compounds could potentially work with the body's own natural painkillers to manage pain," Traynor says.

"We know that conventional strong pain medications ultimately increase the risk of withdrawal symptoms and addiction, which is an especially serious issue with the current prescription drug abuse epidemic in our country. The implications of this work, if it translates to animal studies and then to humans, are highly significant to this area of study."

http://www.sciencedaily.com/releases/2013/06/130610192553.htm

Problems With HIV Drug Side Effects Try Acupuncture

Today's post from pacificcollege.edu (see link below) is a general article about the benefits of acupuncture for relieving the side effects of HIV combination drugs. It also specifically references neuropathy which may be of interest to regular readers. Many younger people, especially in the West, where HIV drugs have been significantly refined to reduce side effects considerably over the last few years, may well shrug their shoulders here and say that they have no side effect issues from combination therapy. However, the vast majority of people across the world who are living with HIV haven't achieved that luxury yet. They have to remain on older drug combinations because of resistance issues if they change, or non-availability and they may well have been living with side effects for so long that it's become part of their daily lives. In these cases, this article may be of value. It is important to consult a qualified acupuncturist who knows what he/she is doing and although it is relatively inexpensive compared to many therapies, cost may still be an issue. However, if you can afford it and feel you may benefit, why not try acupuncture/acupressure therapy. If you achieve relief from the symptoms, you may well be able to cut out, or reduce, other (non-HIV) drugs used to control pain.

Acupuncture to Ease the Side Effects of AIDS Drugs
No date or author provided

As drug cocktails continue to be used as a course of treatment for those who have HIV and AIDS, more patients are suffering through debilitating side effects that are caused by these medications. Often patients complain of a wide range of symptoms including, night sweats, nausea, vomiting, depression, insomnia, anxiety, peripheral neuropathy, muscle pains, and sinus congestion. However, acupuncture is now being used to alleviate some symptoms brought on by the powerful drugs. These treatments have been shown to boost the immune system and help fight the side effects brought on by HIV and AIDS.

Redge Norton of the San Francisco AIDS Foundation uses acupuncture, massage and nutritional therapy to combat the side effects of the powerful drugs. "It really helped to get my appetite back to normal," said Norton. "And I feel more like myself again."

Acupuncture is commonly thought of as an alternative form of therapy, although its history as a treatment for physical ailments predates the era of laboratory-produced drugs by several thousand years. Practitioners of this ancient tradition choose from a variety of treatment modalities when developing an individual treatment regimen for a patient. In addition to acupuncture, these modalities include therapeutic massage, stress reduction techniques, and the application of heat and herbs that is known as moxabustion.

A significant number of primary care providers have come to recognize that such therapies should not be thought of as alternatives to Western medicine, but rather as complementary therapies - therapies used in conjunction with, not instead of, conventional drug treatments.

Acupuncture may help relieve bloating, cramping, and appetite loss among HIV-infected people taking drug cocktails to keep the virus in check. In 2005 a study was presented at a meeting of the International AIDS Society. This study included 50 HIV-infected men and women taking HIV medications. About half had been diagnosed with full-blown AIDS.

At the start of the study, all of the participants complained that the drugs caused at least two digestive side effects: nearly 80% had gas, more than 40% had bloating, 50% had cramps, nearly 50% had appetite loss, and 10% had actually lost weight

The participants then received six weeks of acupuncture. For three weeks the acupuncture included four sites commonly associated with improvement of digestive symptoms, such as nausea, vomiting, and bowel upset. For another three weeks they received acupuncture at four sites nearby sites not noted for affecting digestive conditions.

The patients were unaware of which type of acupuncture they were receiving at any given time.

But after just three weeks of acupuncture treatments, only 60% had two or more digestive symptoms. Both sets of acupuncture points improved digestive symptoms. However, acupuncture at the sites targeting digestive symptoms was more effective in controlling loss of appetite, abdominal cramps, and bloating.

In addition, among the 20% of people who said they weren't taking their AIDS medications as directed at the start of the study, half reported improvement after acupuncture treatment. This points out, states researcher Elizabeth Sommers, research director of the AIDS Care Project/Pathways to Wellness in Boston, since they feel better after acupuncture, people are more likely to take their drugs properly, resulting in better disease control.

In this study, none of the participants complained of side effects from the acupuncture.

Pain, a frequent symptom in people with HIV disease, appears to be particularly responsive to the effects of acupuncture. While the exact mechanisms by which acupuncture relieves pain remain obscure, there is clinical evidence to show that it does work. Specifically, acupuncture has become a popular treatment for people with peripheral neuropathy, which is a common complaint of people with HIV. Neuropathy, or nerve damage, manifests as pain, tingling, or numbness in the extremities, usually the feet. After acupuncture treatments patients report less tingling and more flexibility in the joints.

Among the many attractive features of acupuncture therapy are its safety and its relatively affordable cost. Convenience is also a consideration: it is not necessary to plan one's life around acupuncture treatments, which is an additional benefit to individuals who must plan their lives around their HIV and AIDS drug therapy schedules.

Among the many attractive features of acupuncture therapy are its safety and its relatively affordable cost. Convenience is also a consideration: it is not necessary to plan one's life around acupuncture treatments, which is an additional benefit to individuals who must plan their lives around their HIV and AIDS drug therapy schedules.

http://www.pacificcollege.edu/news/blog/2014/04/26/acupuncture-ease-side-effects-aids-drugs

NEW NANOGEL FOR DRUG DELIVERY

Scientists are interested in using gels to deliver drugs because they can be molded into specific shapes and designed to release their payload over a specified time period. However, current versions aren't always practical because must be implanted surgically.

To help overcome that obstacle, MIT chemical engineers have designed a new type of self-healing hydrogel that could be injected through a syringe. Such gels, which can carry one or two drugs at a time, could be useful for treating cancer, macular degeneration, or heart disease, among other diseases, the researchers say.

The new gel consists of a mesh network made of two components: nanoparticles made of polymers entwined within strands of another polymer, such as cellulose.

"Now you have a gel that can change shape when you apply stress to it, and then, importantly, it can re-heal when you relax those forces. That allows you to squeeze it through a syringe or a needle and get it into the body without surgery," says Mark Tibbitt, a postdoc at MIT's Koch Institute for Integrative Cancer Research and one of the lead authors of a paper describing the gel in Nature Communications on Feb. 19.

Koch Institute postdoc Eric Appel is also a lead author of the paper, and the paper's senior author is Robert Langer, the David H. Koch Institute Professor at MIT. Other authors are postdoc Matthew Webber, undergraduate Bradley Mattix, and postdoc Omid Veiseh.

Heal thyself

Scientists have previously constructed hydrogels for biomedical uses by forming irreversible chemical linkages between polymers. These gels, used to make soft contact lenses, among other applications, are tough and sturdy, but once they are formed their shape cannot easily be altered.

The MIT team set out to create a gel that could survive strong mechanical forces, known as shear forces, and then reform itself. Other researchers have created such gels by engineering proteins that self-assemble into hydrogels, but this approach requires complex biochemical processes. The MIT team wanted to design something simpler.

"We're working with really simple materials," Tibbitt says. "They don't require any advanced chemical functionalization."

The MIT approach relies on a combination of two readily available components. One is a type of nanoparticle formed of PEG-PLA copolymers, first developed in Langer's lab decades ago and now commonly used to package and deliver drugs. To form a hydrogel, the researchers mixed these particles with a polymer -- in this case, cellulose.

Each polymer chain forms weak bonds with many nanoparticles, producing a loosely woven lattice of polymers and nanoparticles. Because each attachment point is fairly weak, the bonds break apart under mechanical stress, such as when injected through a syringe. When the shear forces are over, the polymers and nanoparticles form new attachments with different partners, healing the gel.

Using two components to form the gel also gives the researchers the opportunity to deliver two different drugs at the same time. PEG-PLA nanoparticles have an inner core that is ideally suited to carry hydrophobic small-molecule drugs, which include many chemotherapy drugs. Meanwhile, the polymers, which exist in a watery solution, can carry hydrophilic molecules such as proteins, including antibodies and growth factors.

Long-term drug delivery

In this study, the researchers showed that the gels survived injection under the skin of mice and successfully released two drugs, one hydrophobic and one hydrophilic, over several days.

This type of gel offers an important advantage over injecting a liquid solution of drug-delivery nanoparticles: While a solution will immediately disperse throughout the body, the gel stays in place after injection, allowing the drug to be targeted to a specific tissue. Furthermore, the properties of each gel component can be tuned so the drugs they carry are released at different rates, allowing them to be tailored for different uses.

The researchers are now looking into using the gel to deliver anti-angiogenesis drugs to treat macular degeneration. Currently, patients receive these drugs, which cut off the growth of blood vessels that interfere with sight, as an injection into the eye once a month. The MIT team envisions that the new gel could be programmed to deliver these drugs over several months, reducing the frequency of injections.

Another potential application for the gels is delivering drugs, such as growth factors, that could help repair damaged heart tissue after a heart attack. The researchers are also pursuing the possibility of using this gel to deliver cancer drugs to kill tumor cells that get left behind after surgery. In that case, the gel would be loaded with a chemical that lures cancer cells toward the gel, as well as a chemotherapy drug that would kill them. This could help eliminate the residual cancer cells that often form new tumors following surgery.

"Removing the tumor leaves behind a cavity that you could fill with our material, which would provide some therapeutic benefit over the long term in recruiting and killing those cells," Appel says. "We can tailor the materials to provide us with the drug-release profile that makes it the most effective at actually recruiting the cells."

NEW HORIZON IN HEART FAILURE INVESTIGATIONAL DRUG POISED TO CHANGE CARDIOLOGY

An investigational new heart failure drug could be poised to change the face of cardiology based on Hot Line results presented today at ESC Congress 2014

Findings from the PARADIGM-HF trial, published simultaneously in the New England Journal of Medicine, "are extraordinarily powerful and compelling; they are destined to change the management of patients with chronic heart failure for years to come," said Milton Packer, MD, co-primary author of the study from University of Texas Southwestern Medical Center, in Dallas, Texas USA.

"This really is an astonishing result and a real breakthrough for patients with heart failure," added John McMurray, MD, the other co-primary author, from the University of Glasgow, UK.

The new agent, an angiotensin receptor-neprilysin inhibitor (ARNI) known as LCZ696, has already been granted Fast Track status by the United States Food and Drug Administration (FDA) -- a designation which can expedite the review of new medicines intended to treat serious or life-threatening conditions. Fast Track designation also allows for rolling submission in the US, which Novartis said it expects to complete by the end of 2014. The company said it aims to file in Europe in early 2015.

"To say that we are excited is an understatement. We are absolutely thrilled," said Dr. Packer.

"Given the survival advantage of LCZ696 over currently available drugs, once this drug becomes available, it would be difficult to understand why physicians would continue to use traditional angiotensin converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for the treatment of heart failure."

PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) first made headlines this spring when the trial was stopped early by an independent data monitoring committee based on evidence of the "overwhelming benefit" of LCZ696 compared to enalapril, an ACE inhibitor.

"We were surprised and delighted that the magnitude of the superiority was so great that the trial was stopped early by the ethical committee. That was an amazing event," said Dr. Packer.

Today, full details of the findings are being released for the first time.

"The magnitude of the advantage of LCZ696 over enalapril on cardiovascular mortality was at least as large as that of enalapril over placebo during long-term treatment," Dr. Packer reported. "This robust finding provides strong support for using this new approach instead of ACE inhibitors or ARBs in the treatment of chronic heart failure."

PARADIGM-HF randomized 8,399 patients with class II to IV heart failure and an ejection fraction if 40% or less to either LCZ696 200 mg twice daily (n=4,187), or enalapril 10 mg twice daily (n=4,212), in addition to recommended therapy.

When the trial was stopped early, after a median follow-up of 27 months, death from cardiovascular causes or hospitalisation for heart failure (the primary composite outcome) had occurred in 21.8% of the LCZ696 group and 26.5% of the enalapril group (hazard ratio [HR] 0.80; p=0.0000002).

Compared to enalapril, LCZ696 reduced the risk of death from cardiovascular causes by 20% (13.3% vs 16.5%; HR 0.80; p<0.0001), and the risk of hospitalisation for heart failure by 21% (12.8% vs 15.6%; HR 0.79; p<0.0001), noted Dr. Packer. This effect was consistent across all prespecified subgroups.

Secondary outcomes were also significantly improved by LCZ696, including all-cause mortality (17.0% vs 19.8%; HR 0.84; p<0.001) and symptoms and physical limitations of heart failure measured on the Kansas City Cardiomyopathy Questionnaire (p=0.001).

"The superiority of LCZ696 over enalapril was not accompanied by important safety concerns," added Dr. Packer. The LCZ696 group had more symptomatic hypotension compared to the enalapril group (14% vs 9.2%, p< 0.001) however this rarely required the discontinuation of treatment. In fact, fewer patients in the LCZ696 group stopped their study medication for any adverse event (10.7% vs 12.3%, P=0.03).

Importantly, LCZ696 was not associated with an increased risk of serious angioedema, which was the main safety concern observed with a related medication -- omapatrilat -- in the OVERTURE trial.

Omapatrilat's association with life-threatening angioedema is related to its inhibition of ACE, neprilysin and aminopeptidase P, whereas LCZ696 avoids inhibition of ACE and aminopeptidase P. "LCZ696 was specifically designed to minimise the risk of serious angioedema by combining the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan," explained Dr. Packer.

Findings of the PARADIGM-HF trial are particularly striking when considered in the context of the current standard of care in heart failure, concluded Professor McMurray.

"The superiority of LCZ696 wasn't over placebo -- it was over the gold-standard dose of the gold-standard ACE inhibitor, the absolute corner-stone of guideline-recommended, conventional therapy," he said. "On top of that, these incremental benefits were obtained in patients fully treated with the other key pharmacological therapies for this condition such as beta-blockers and mineralocorticoid receptor antagonists. All that you can ask of any new therapy in heart failure (or other chronic diseases) is to make patients live longer, stay out of hospital and feel better -- and those are exactly the benefits we demonstrated with LCZ696."

New Discovery Curbs Nerve Pain Without Drug Side Effects

Today's post from sciencedaily.com (see link below) is one of those complex technical ones that often leave us scratching our heads to wonder how it could possible affect our own personal situations. However, if you take a little time to read it, you should get the gist of what it's saying and what the implications are. It starts off with a neuropathy-patient-friendly call for treatments that work well on people and not just laboratory mice. We are so used to the newest developments being announced at the rodent-testing stage, that we lose faith that they will ever be translated to human treatment. This article tries to show that the gulf between lab-rats and humans in this case, is not so large after all. Worth a read.

Potent approach shows promise for chronic pain
Inhibitor discovered through human, mouse genetic studies curbs pain without narcotic side effects 
Date:June 17, 2015 Source:Boston Children's Hospital

Non-narcotic treatments for chronic pain that work well in people, not just mice, are sorely needed. Drawing from human pain genetics, an international team led by Boston Children's Hospital demonstrates a way to break the cycle of pain hypersensitivity without the development of addiction, tolerance or side effects.

Their findings, reported June 17 in the journal Neuron, could lead to treatments for chronic pain conditions caused by nerve damage, such as diabetic peripheral neuropathy (DPN) and post-herpetic neuralgia (PHN), as well as chronic inflammation, like rheumatoid arthritis. Current treatments provide meaningful pain relief in only about 15 percent of patients.

"Most pain medications that have been tested in the past decade have failed in phase II human trials despite performing well in animal models," notes Clifford Woolf, MD, PhD, director of Boston Children's F.M. Kirby Neurobiology Center and a co-senior investigator on the study with Michael Costigan, PhD. "Here, we used human genetic findings to guide our search from the beginning."

In 2006, Costigan, Woolf and colleagues showed in Nature Medicine that people with variants of the gene for GTP cyclohydrolase (GCH1)--about 2 percent of the population--are at markedly lower risk for chronic pain. GCH1 is needed to synthesize the protein tetrahydrobiopterin (BH4), and people with GCH1 variants produce less BH4 after nerve injury. This suggested that BH4 regulates pain sensitivity.

"We wanted to use pharmacologic means to get the same effect as the gene variant," says Alban Latremoliere, PhD, also of Boston Children's Kirby Center, who led the current study along with Woolf and Costigan.

In a "reverse engineering" approach, the researchers modeled the human biology in mice. They first showed that mice with severed sensory nerves produce excessive BH4, churned out both by the injured nerve cells themselves and by macrophages--immune cells that infiltrate damaged nerves and inflamed tissue. Mice engineered to make excess BH4 had heightened pain sensitivity even when they were uninjured, suggesting that BH4 is sufficient to produce pain. On the flip side, mice that were genetically unable to produce BH4 in their sensory nerves had decreased pain hypersensitivity after peripheral nerve injury.

"We then asked, if we could reduce production of BH4 using a drug, could we bring about reduction of pain?" says Latremoliere.

The answer was yes. The researchers blocked BH4 production using a specifically designed drug that targets sepiapterin reductase (SPR), a key enzyme that makes BH4. The drug reduced the pain hypersensitivity induced by the nerve injury (or accompanying inflammation) but did not affect nociceptive pain--the protective pain sensation that helps us avoid injury.

Fine-tuning pain relief

Because BH4 is active all over the body, with important roles in the brain and blood vessels, the goal of any treatment would be to dial down excessive BH4 production, but not eliminate it entirely. Latremoliere and colleagues showed that blocking SPR still allowed minimal BH4 production through a separate pathway and reduced pain without causing neural or cardiovascular side effects.

"Our findings suggest that SPR inhibition is a viable approach to reducing clinical pain hypersensitivity," says Woolf. "They also show that human genetics can lead us to novel disease pathways that we can probe mechanistically in animal models, leading us to the most suitable targets for human drug development."

Story Source:

The above post is reprinted from materials provided by Boston Children's Hospital. Note: Materials may be edited for content and length.

Journal Reference:
Clifford J. Woolf et al. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron, June 2015 DOI: 10.1016/j.neuron.2015.05.033

http://www.sciencedaily.com/releases/2015/06/150617135409.htm

Drug treatment for sciatic nerve pain

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Neuropathy Drug Treatment An Assessment 2012

Today's post comes from drmarcspitz.com (see link below), who regular readers of this blog may be familiar with. He is a podiatrist from California who always talks sense about neuropathy and gives a totally unbiased and non-commercial view of the topic at hand. This article sums up the current main drug-treatment approaches to neuropathy and is a good guide to how and why these drugs are used. His advice to talk any treatment over with your doctor is very important - these drugs are not M & M's.

Treating Neuropathy with Neurontin, Lyrica or Cymbalta-the Pros and Cons

This entry was posted on Sunday, May 13th, 2012

Read any medical journal or peruse any medical friendly websites, it seems that the three most consistently recommended medications for the treatment peripheral neuropathy are Neurontin, Lyrica or Cymbalata. You would think these drugs are the wonder drugs for neuropathy-this not quite accurate. Actually there are many drawback to these medications-let’s take a closer look.

Neurontin-The #1 prescribed medication for neuropathy

Neurontin is commonly prescribed medication for neuropathy pain-that is neuropathy in the feet.
Neurontin (generic name is gabapentin) is an oral medication approved by the FDA for the treatment of seizure for patients who have epilepsy. Gabapentin is classified as an anticovulsant medication. It is also indicated to help relive nerve pain associated with shingles (also called postherpetic neuralgia). While this medication is one of the most prescribed, it was a not developed as a primary treatment for any type of peripheral neuropathy.
There are many side effects associated with the drug with most being, drowsiness, memory problems, lethargy and a sensation of fogginess.” There are many other side effects as well including, allergic reaction, dizziness, headache to name just a few. Is it effective in reducing neuropathy pain?-the verdict is not out. There are wide variety of reported results-however in some studies Neurontin has been reported to be effective less than 50% of the time.

Lyrica-The New Neurontin

Lyrica is chemically related to Neurontin.. It also has been approved by the FDA for diabetic neuropathy-any of use of Lyrica to reduce neuropathy pain other than diabetes is called “off-label.” It is also prescribed for other conditions including pain form shingles (postherpetic neuralgia), fibromyalgia and as adjunctive therapy (meaning working in combination with other medications). It will not restore feeling in the foot nor will it restore damaged nerves.

Cymbalta- #3 but closing fast

Cymbalta is an antideoressant medication. It is used to treat major depressive disorders and general anxiety disorder. It is in the category of antidepressants called selective serotonin and norepinephrine reuptake inhibitors—SSNRI’s. Cymbalta has also been approved by the FDA to manage pain associated with diabetic peripheral neuropathy. It is used “off label” to treat other types of neuropathy pain.
Like the other medications mentioned, Cymbalta will not reverse damage but may reduce neuropathy pain. It will not restore feeling in the foot.
Cymbalta will not reverse damage but may reduce pain caused by diabetic peripheral neuropathy. Side effects include drowsiness, weight gain, nausea constipation or diarrhea, dry mouth sleep disturbances among many others.

Should I take any of these drugs for my neuropathy?
Great question and there is no right answer. You have to weigh the benefits versus side effects. Some of my patients relate that the adverse effects of these drugs are actually as a bad or worse than the neuropathy pain. Talk to your physician before starting any of these medications and express your concerns. A word of caution-do not stop taking any of these medications without informing your doctor as sudden withdrawal can lead to seizures.

http://drmarcspitz.com/blog/2012/05/13/treating-neuropathy-with-neurontin-lyrica-or-cymbalta-the-pros-and-cons/

Colon Cancer Drug may cause Neuropathy

It's of course pretty well known that chemotherapy can leave patients with neuropathy as a side effect but how does this have anything to do with HIV- patients, besides the normal percentage who unfortunately contract a form of cancer?
One of the fastest growing cancers, especially for HIV positive men, is colon or rectal cancer and this associated with the alarming rise in HPV infections means that significant numbers of HIV patients are needing cancer treatment.
One of the best known drugs aimed specifically at colon cancer is Oxaliplatin and its success rates make it more and more popular but there's a sting in the tail and that is permanent and debilitating neuropathy. Once more HIV patients are being faced with unexpected extra problems, something we're long used to but the reality is that neuropathy is the price that sometimes has to be paid for extending your life. This article from sciencedaily.com (see link below) explains the pros and cons of using Oxaliplatin. Once again, a serious discussion with the oncologist, neurologist and hiv-specialist is necessary - don't be palmed off without the facts - in that way you avoid nasty surprises!

Popular Colorectal Cancer Drug May Cause Permanent Nerve Damage, Study Suggests
ScienceDaily (Sep. 28, 2011)

Oxaliplatin, a platinum-based anticancer drug that's made enormous headway in recent years against colorectal cancer, appears to cause nerve damage that may be permanent and worsens even months after treatment ends. The chemotherapy side effect, described by Johns Hopkins researchers in the September issue of Neurology, was discovered in what is believed to be the first effort to track oxaliplatin-based nerve damage through relatively cheap and easy punch skin biopsies.

The Johns Hopkins investigators emphasize that the drug therapy clearly improves length of survival in advanced cancer by months to years, and that the goal of their new study is to find ways of preventing or slowing the damage through nerve-protective therapies identfied through simple skin testing.

Many patients who take oxaliplatin report bothersome neurological side effects, including pain in the hands and feet and a numbness or tingling in the throat that affects swallowing, according to study leader Michael Polydefkis, M.D., M.H.S., associate professor of neurology at the Johns Hopkins University School of Medicine and director of the EMG Laboratory and Cutaneous Nerve Laboratory at Johns Hopkins Bayview Medical Center. Though these symptoms develop over time in the majority of patients, some report neuropathies as early as when the drug is first infused.

To get a better sense of how oxaliplatin affects nerve cells, Polydefkis and his colleagues recruited eight cancer patients about to begin oxaliplatin treatment at The Johns Hopkins Hospital. All had been diagnosed with advanced colon cancer.

Before their first oxaliplatin infusion, each patient underwent a comprehensive neurological examination, including nerve conduction testing, a clinical exam to look for signs of nerve damage, and a punch biopsy that removed tiny (3-mm diameter) portions of skin near their knees and ankles. Once oxaliplatin treatment began, consisting of infusions over two days once every two weeks for 12 cycles, the researchers performed the same tests after 30, 90 and 180 days. Another 180 days after they finished with treatment, the patients received one final exam.

Test results showed that each of the patients' nerve function and neuropathy symptoms worsened over time and that results from the punch skin biopsies neatly mirrored the side effect arc. Using a microscope, the researchers saw that nerve cells' long extensions, called axons, degenerated over the course of oxaliplatin therapy. This progression persisted after treatment stopped. Even 180 days after their last doses, seven out of the eight patients' axons continued to wither.

"This drug has rapidly become the standard of care for people with advanced colon cancer, but we really knew little about how oxaliplatin affects nerves over time," he says. "With people living longer lives on oxaliplatin, it's important to know more about these neurological side effects so patients and their physicians can make educated choices on how this drug is used, and perhaps suggest ways to limit the damage."

The new study strongly suggests that punch skin biopsies could be an easy and inexpensive way to follow nerve cell degeneration, a crucial prerequisite for testing the effectiveness of drugs currently in development to trace, prevent or slow nerve damage.

"Skin biopsies can be done pretty easily, uniformly and cheaply anywhere, including hospitals, doctors' offices and clinics, and those places can have the tissue sent to Hopkins for analysis," Polydefkis says. "High-quality neurological testing isn't nearly as easy or economical to do, so it's possible that the biopsies could play a pivotal role in bringing neuroprotective drugs to fruition."

Other Johns Hopkins researchers who participated in this study include Ahmet Z. Burakgazi, M.D., Wells Messersmith, M.D., Dhananjay Vaidya, M.D., Ph.D., Peter Hauer, B.S., and Ahmet Hoke, M.D., Ph.D.

http://www.sciencedaily.com/releases/2011/09/110928105911.htm

New Drug Z944 For Neuropathic Pain

Today's post from allfordrugs.com (see link below) announces a new drug which may soon become available for treating neuropathy. It all depends on the outcomes fo the trials of course, so it may be some years before it appears on your doctor's prescription pad but it's always useful knowing what's in the pipeline. This one has the unattractive name of Z944 at the moment but that will undoubtedly change when its patented. The article itself may well seem like Martian for most people but the important words to remember are 'calcium channel blocker' because many of the drugs in current use or development are also calcium or sodium channel blockers. Googling will provide more information on this sort of pain signal blocker. 

Zalicus starts Phase Ib clinical trial of neuropathic pain drug phase 2, 
Nov 14th 2013
 

Biopharmaceutical firm Zalicus has started a Phase Ib clinical trial of Z944, a novel oral T-type calcium channel blocker, for the treatment of neuropathic pain.

The company expects to release the results from the laser-evoked potentials (LEP) study in the fourth quarter of 2013.

The study is designed to offer both objective and subjective data on a drug’s ability to modulate pain signalling.

http://www.drugdevelopment-technology.com/news/newszalicus-starts-phase-ib-clinical-trial-of-neuropathic-pain-drug

Z944 is a novel, oral, T-type calcium channel modulator that we are developing for pain.
Z944, an oral T-type Calcium Channel Modulator

Z944 is a novel, oral, state-dependent, selective T-type calcium channel modulator that has demonstrated efficacy in multiple preclinical inflammatory pain models and in a Phase 1b experimental model of pain. T-type calcium channels have been recognized as key targets for therapeutic intervention in a broad range of cell functions and have been implicated in pain signaling. Zalicus is planning to advance a modified release formulation of Z944 through further clinical development.

The wide distribution of T-type calcium channels found in brain, heart, endocrine cells and other tissues provides the possibility of developing therapeutics for multiple indications, including treatment of pain. Zalicus has utilized its expertise in this field to successfully discover high affinity, selective and orally available compounds, such as Z944, that show promise for further development.

T-type Calcium Channel Modulators

T-type, or transient-type (referring to the length of time activated), calcium channel modulators target low-voltage-activated, calcium channels. These channels have been recognized as critical components in numerous cell functions and have been implicated in the frequency and intensity of pain signals. Zalicus is investigating compounds to modulate T-type calcium channel signaling in the treatment of pain. Our orally-administered T-type calcium channel blockers have shown efficacy in animal models of acute, chronic and visceral pain, as well as other indications.

patent

WO2009146540

http://www.google.com/patents/WO2009146540A1

compd may be

N-[1-(N-tert-Butylcarbamoylmethyl)piperidin-4-ylmethyl]-3-chloro-5-fluorobenzamide

http://www.allfordrugs.com/2013/11/14/zalicus-starts-phase-ib-clinical-trial-of-neuropathic-pain-drug/