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ScienceDaily are reporting: Trial Success For Diabetic Nerve Therapy
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A potentially ground-breaking treatment for nerve damage caused by diabetes has shown promising results in preclinical and early patient trials.
The University of Manchester team has discovered that injection of a novel therapeutic that works by stimulating a person's genes may prevent nerve damage – primarily to the hands and feet – caused by the disease.
The positive preclinical results – reported in the journal Diabetes – are further evidence that the research could lead to a new treatment for diabetic nerve damage or 'neuropathy'; initial-stage clinical trials on patients in the United States have also been encouraging.
Lead researcher Professor David Tomlinson says the study has massive potential for managing the condition and preventing thousands of foot amputations each year.
"The vast majority of non-traumatic hand and foot amputations carried out in UK hospitals are caused by diabetes and there are currently no treatments available to prevent or slow the progress of nerve disease in diabetic patients," he said.
"Our tests have shown that a single injection of a DNA-binding protein protected nerve function, stimulated nerve growth and prevented tissue damage that in humans can lead to limb loss."
An estimated 50 per cent of patients with long-term diabetes develop some form of neuropathy that can cause numbness and sometimes pain and weakness in the hands, arms, feet and legs. Progression to amputation is not inevitable, but it is always a threat.
Problems may also occur in other organs, including the heart, kidneys, sex organs, eyes and digestive tract.
"Diabetic neuropathy is a major problem in insulin-dependent diabetes, particularly in patients who have had the disease for a period of time," said Professor Tomlinson, who is based in the University's Faculty of Life Sciences.
"Our approach to gene therapy is quite different to previous attempts at treatment: we use a DNA-binding protein called ZFP TFTM to poke life into the patient's own genes and produce a growth factor that has a role in nerve protection and regeneration.
"As the data in the paper demonstrate, we have had some striking success."
The US clinical trials – carried out by Professor Tomlinson's collaborators at biotech firm Sangamo BioSciences Inc – have also been encouraging with the only adverse event reported being mild injection-site reaction in four of the 12 diabetic patients tested, all of which resolved quickly.
"We are delighted by the progress of our clinical programme in diabetic neuropathy and by the reception it has received from the medical and scientific community," said Edward Lanphier, Sangamo's President and CEO.
"We believe our DNA-binding protein may provide a novel and much-needed therapeutic approach to diabetic neuropathy and optimistically look forward to the next stage of development of this novel therapeutic when phase-two clinical trials start later this year."
The incidence of diabetes, a condition in which the amount of glucose in the blood is too high, is increasing dramatically with the World Health Organisation estimating that some 300 million people worldwide could be affected by 2025.
The causes of diabetic neuropathy are not fully understood but researchers investigating the effect of glucose on nerves believe it is likely to be a combination of factors.
Favorable Results With Lacosamide For Use In Diabetic Neuropathic Pain
04 Jun 2006
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The primary endpoint for the lacosamide target dose was at the statistically significant level when the investigational agent was evaluated for the treatment for painful diabetic neuropathy in a recent phase 3 trial.
Aziz Shaibani, MD, Director of the Nerve and Muscle Center of Texas in Houston, presented the data recently at the 25th Annual Meeting of the American Pain Society (APS).
Lacosamide is being studied as an anticonvulsant with potential for reducing diabetic neuropathic pain. Diabetic neuropathic pain affects about eleven million diabetics worldwide, and the incidence of the condition increases with age. Nearly 50 percent of individuals who have had diabetes for over 25 years will experience some symptoms of painful diabetic neuropathy.
Dr. Shaibani's team randomized 469 patients with pain due to distal diabetic neuropathy to twice-daily oral lacosamide or placebo across four different treatment arms: placebo; lacosamide, 200 mg/d; lacosamide, 400 mg/d; and lacosamide 600 mg/d, in a 1:2:2:2 ratio, respectively.
Subjects were treated for a maximum of 20 weeks.
The primary efficacy variable was the within-subject change in the average daily pain score from the baseline week to the last four weeks of the 12-week maintenance phase using the widely validated Likert Scale.
Results showed that the target lacosamide dose of 400 mg/d approached statistical significance, p=0.0507.
Lacosamide at 400 mg/d and 600 mg/d significantly lowered pain scores throughout the treatment and maintenance periods.
The 200 mg/d and 400 mg/d doses were better tolerated than the 600 mg/d dose.
Elsewhere at the meeting, researchers reported that lacosamide has low potential for drug-drug interactions.
The study was sponsored by Schwarz Pharma in Monheim, Germany.
Press Release: New Phase III Trial Shows Positive Outcome of lacosamide in Patients with Diabetic Neuropathic Pain
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Brussels (Belgium), 11 December 2007 at 7:00 AM (CET): UCB announced today positive results from a Phase III trial evaluating lacosamide (400 mg per day) in the treatment of diabetic neuropathic pain. With a standard titration regimen, the trial met its primary objective with sustained and statistically significant reduction in average daily pain scores.
"These new results add to the data from earlier clinical studies showing the benefit of lacosamide in this painful and common complication of diabetes," said Iris Loew-Friedrich, MD, PhD, Global Head of Development, UCB Group.
The randomised, double-blind, placebo controlled trial in 551 patients with diabetic neuropathic pain was designed to evaluate the efficacy and safety of lacosamide (400mg per day) in two different titration schemes: a standard titration regimen in which patients reached their target dose at day 22, and a fast titration scheme in which the target dose was reached at day 8.
The primary efficacy results showed that the change in the average daily pain score as measured from baseline to the last four weeks of the 12-week maintenance period, was significantly greater with lacosamide 400mg per day given in standard titration than placebo (p=0.0410). The change in pain score with the lacosamide fast titration regimen was numerically better than placebo but did not reach statistical significance (p=0.2902). The median time to achieve sustainable pain relief was 10 and 11 days for the lacosamide standard and fast titration regimens, respectively compared with 31 days for the placebo group. Lacosamide was generally well tolerated. The incidences of adverse events were higher in the lacosamide fast titration group than in the standard titration group. The most common adverse events (>=5%) in this trial were dizziness, nausea, headache, nasopharyngitis and vertigo.
The results from this trial will support the dossiers filed for lacosamide in diabetic neuropathic pain which were submitted to the European and U.S. regulatory authorities earlier this year. Data from this trial will be submitted for presentation at upcoming international scientific meetings.
About Diabetic Neuropathic Pain [1],[2]: Diabetic Neuropathic Pain is a painful and potentially debilitating condition, resulting from damage or dysfunction to the peripheral nervous system as a result of diabetes or impaired glucose tolerance. The condition is often characterized by a stabbing or burning sensation in the legs, feet, and/or hands. With the overall prevalence of diabetes in the U.S. estimated at 20.8 million people, it is thought that as many as 7.7 million have some degree of diabetic neuropathic pain.
About lacosamide [3],[4]: lacosamide has a novel and dual mode of action. It selectively enhances slow inactivation of sodium channels and interacts with the neuroplasticity-relevant target - collapsin-response mediator protein-2 (CRMP-2).
References
[1.] Beyreuther BK, Freitag J, Heers C et al. Lacosamide: a review of preclinical properties.CNS Drug Reviews 2007;13 (1), 21-42
[2.] Nicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care 2006;12, S256-S262
[3.] Heers, C, Beyreuther, B., Freitag, J., Lees, G. Errington A., Stöhr, T.: Lacosamide selectively enhances sodium channel slow inactivation. Poster Presentation, 11th EFNS, Brussels, 2007
[4.] Freitag, J., Beyreuther, B., Heers, C, Stöhr, T. Lacosamide interacts with collapsin response mediator protein 2 (CRMP 2). Poster Presentation, 11th EFNS, 2007
Neuritin Mediates Nerve Growth Factor–Induced Axonal Regeneration and Is Deficient in Experimental Diabetic Neuropathy
Eugenia Karamoysoyli, Rebecca C. Burnand, David R. Tomlinson, and Natalie J. Gardiner Diabetes 57:181-189, 2008
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OBJECTIVE—Axonal regeneration is defective in both experimental and clinical diabetic neuropathy, contributing to loss of axonal extremities and neuronal dysfunction. The mechanisms behind this failure are not fully understood; however, a deficit in neurotrophic support and signaling has been implicated.
RESEARCH DESIGN AND METHODS—We investigated the expression of neuritin (also known as candidate plasticity gene 15, cpg15) in the sensory nervous system of control rats and rats with streptozotocin (STZ)-induced diabetes using microarray PCR, Western blotting, and immunocytochemical analysis. The functional role of neuritin in sensory neurons in vitro was assessed using silencing RNA.
RESULTS—Neuritin was expressed by a population of small-diameter neurons in the dorsal root ganglia (DRG) and was anterogradely and retrogradely transported along the sciatic nerve in vivo. Nerve growth factor (NGF) treatment induced an increase in the transcription and translation of neuritin in sensory neurons in vitro. This increase was both time and dose dependent and occurred via mitogen-activated protein kinase or phosphatidylinositol-3 kinase activation. Inhibition of neuritin using silencing RNA abolished NGF-mediated neurite outgrowth, demonstrating the crucial role played by neuritin in mediating regeneration. Neuritin levels were reduced in both the DRG and sciatic nerve of rats with 12 weeks of STZ-induced diabetes, and these deficits were reversed in vivo by treatment with NGF.
CONCLUSIONS—Manipulation of neuritin levels in diabetes may therefore provide a potential target for therapeutic intervention in the management of neuropathy.
that was very helpful ...do you have a paper on the effect of opsite on neuropathy????
have most other papers thru cochrane ,pubmed etc but haven't found this one yet ...could keep looking but if you know could save me lotsof time...thanks
t..do you have a paper on the effect of opsite on neuropathy????
The original publication was this: Application of OpSite film: a new and effective treatment of painful diabetic neuropathy.
Foster AV, Eaton C, McConville DO, Edmonds ME. Diabet Med. 1994 Oct;11(8):768-72.
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The aim of the study was to assess the effect of application of OpSite dressings on the pain and quality of life in 33 patients with chronic diabetic neuropathy. The effect of OpSite was compared with no treatment. After a run-in period of 2 weeks, OpSite was applied to one of the painful legs for 4 weeks. This was followed by another period of 4 weeks when OpSite was switched to the opposite leg. Pain was assessed by visual analogue scale and the primary analysis variable was within patient difference in pain between OpSite leg and no treatment leg at week 4 corrected for baseline. Secondary variables were paracetamol pill ingestion and the quality of life dimensions, sleep, mobility, contact discomfort, appetite, and mood. Changes in these variables from baseline to weeks 4 and 8 were analysed. There was a significantly greater reduction in pain in the OpSite treated limbs than the control limbs (p < 0.001). By week 4 paracetamol intake also declined significantly (p = 0.034) and patients experienced a significant improvement in contact discomfort, sleep, mood, appetite, and mobility (p < 0.002 for all 5 variables). OpSite appeared to alleviate the pain associated with diabetic painful neuropathy and thus improved patients' quality of life.
Trial Success For Diabetic Nerve Therapy
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