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Research & Development

Drug Development Issues Related To New Compounds For Treating Neuropathic Pain And Neuropathy Are Presented Here.

Phenytoin cream normalizes neural overactivity in skin in neurogenic inflammation

Phenytoin cream is a newly developed cream by the Institute of Neuropathic Pain and protected by 2 patents, filed on December 6th, 2016. The cream contains 5 or 10% phenytoin and here we picture one of the mechanisms of action, via the keratinocyte.

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Low-grade inflammation in Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS); treatment by palmitoylethanolamide supplement

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a disorder difficult to understand for many, especially for doctors who too often think this disorder does not exist. Well it does! Modern neurobiological research clearly found new insights in the cause of this disease. New findings point out that inflammatory pathways and immunity derangements play an important role in the pathophysiology of Myalgic Encephalomyelitis […]

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Chronic prostatitis/chronic pelvic pain syndrome, neurologic inflammation and autoimmune disease and palmitoylethanolamide

In a recent review it was highlighted that symptoms of chronic prostatitis/CPPS appear to cluster into a group with primarily pelvic or localized disease,  as well as in a group with more systemic symptoms, such as generalized pain disorders. There seems to exist a cluster of chronic pain conditions related to chronic inflammation, and in this cluster we can […]

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Visceral pain: a forgotten topic

Prof. Fernando Cervero from Montreal, Canada discussed at the EFIC 2013 in Florence an underserved but very important topic: visceral pain. Visceral pain is very underserved, as patients visit often organ specialists not interested in pain itself, but directly focussing on the underlying illness. However, as visceral pain is a cinderella in the pain field, […]

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Visceral pain: basic mechanism and science

At the 2013 EFIC congress on pain in FLorence the Ulf Lindblom Special Lecture was dedicated to visceral pain, and presented by Prof. dr. F. Cervero from The Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada. Cervero pointed out that visceral pain is a prominent symptom of many clinical conditions. Visceral […]

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Neuropathic pain: microglia controls neuronal network excitability

Microglia-neuron interactions are leading to altered neural network excitability, the pathogenetic base of neuropathic pain. Modern research demonstrates that one of the key factors driving neurons nuts in neuropathic pain is the inflammatory compound ‘Brain-derived neurotrophic factor (BDNF)’, released by microglia. [1] Microglial BDNF plays a key role in controlling neuronal excitability by causing disinhibition. This […]

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NMDA receptor: target for new developments in neuropathic pain

The NMDA receptor (NMDAR) received a new wave of attention as a target receptor for the development of new drugs for the treatment of neuropathic pain. A substantial body of data supports the expectation that a safe, potent, N-methyl-D-aspartate receptor (NMDAR) blockers would offer symptomatic relief from neuropathic pain. NMDAR stimulation is linked to sensitization of dorsal horn neurons and thus has a direct link to pain and hyperalgesia. Here some of these new R&D activities related to NMDAR ligands. 

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Ketamine in neuropathic pain

ketamine.jpegKetamine is an old drug, and has been in clinical practice for nearly 40 years, but we should not forget this drug for the treatment of neuropathic pain, and we should not be too conservative exploring ketamine as a treatment for otherwise treatment refractory neuropathic pain patients. Ketamine can be used in various ways, as infusions, oral, rectal, intranasal and transdermal. 

As an analgesic drug, doses used are much lower compared to dose-ranges used in anesthesiological practices. Furthermore, the whole story of S-ketamine being less psychoiactive compared to R-ketamine is based on old literature, with very small groups of patients, non-relaible biological read outs, such as the EEG and animal studies with very little relevance for the human species.  

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Avigen AV411 as a glia modulator in neuropathic pain

AV411 is orally bioavailable small molecule, which is characterized as a glial attenuator, that suppresses pro-inflammatory cytokines IL-1 beta, TNF alpha, and IL-6, and may upregulate the anti-inflammatory cytokine IL-10. It is under devellopment by Avigen, Inc. (Nasdaq:AVGN), a biopharmaceutical company developing innovative therapies for the treatment of neurological conditions.

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Astra-Zeneca compound AZD2423 fails in neuropathic pain: posttraumatic neuralgia.

The Astra-Zeneca compound AZD2423, a novel chemokine receptor 2 (CCR2) antagonist, fails in treating neuropathic pain in posttraumatic neuralgia. This is the result of a phase II trial dose-finding in 133 patients with posttraumatic neuralgia. Patients were equally randomized to 28days’ oral administration of 20mg AZD2423, 150mg AZD2423 or placebo.

 

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Patients critical about doctos’s knowledge of neuropathic pain in SCI

How do community-dwelling individuals with a traumatic spinal cord injury (SCI) see their chronic pain and how do they acquiring information. In this study the authors used a semi-structured interview and interviewed 12 individuals experiencing sipinal cord injury (SCI)-related chronic pain. This is neuropathic pain of central origine.

 

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Santhera’s Catena® in Leber’s Hereditary Optic Neuropathy

Santhera Pharmaceuticals Holding AG will present newest clinical data related to the results of a clinical trial of Catena® in Leber’s Hereditary Optic Neuropathy (LHON). Catena® is the first drug that has been evaluated in arandomized, placebo-controlled study in LHON. Catena® might protect the retinal and optic nerve cellsand thereby delay, lessen or prevent vision loss. LHON is a rare neuropathy of the eye nerves, estimated with 20,000 patients in Europe and in the United States.

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Palmitoylethanolamide (PEA), an ALIAmide regulating mast cells

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Identification of palmitoylethanolamide (PEA) as regulatory mechanism for the metabolism of mast cells by Nobel Price Laureate Rita Levi Montalcini in 1993, and it’s use as a analgesic and anti-inflammatory compound

Searching for non psychoactive Cannabinoids our clinic identified in 2010 the small molecule palmitoylethanolamide (PEA) as a potent novel and promising analgesic and anti-inflammatory agent. This molecule has been developed based on the work and insights of Rita Levi Montalcini, as an off spin of her work with nerve growth factors.

As PEA, trade names PeaPure and Normast, is gaining more and more international recognition as a break through molecule in the treatment of chronic pain and inflammation, it is worth while to shortly analyze how the mast cell modulation concept, palmitoylethanolamide and the ALIA concepts came into existence.

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Bupivacaine Patch, Eladur, in Post- Herpetic Neuralgia

Bupivacaine is a locally acting anesthetic agent, therefore systemic plasma concentrations is not relevant. The company Durect is  developing a transdermal bupivacaine patch (ELADUR) based on their proprietary TRANSDUR transdermal technology intended to provide continuous delivery of bupivacaine for up to three days from a single patch. ELADUR might have several potential advantages compared with currently marketed lidocaine patches, including extended duration of action and better wearability.

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AGN-209323 from Bristol-Myers Squibb in neuropathic pain

Bristol-Myers Squibb Company (NYSE: BMY) and Allergan, Inc. (NYSE: AGN) announced in March 2010 a global agreement for the development and commercialization of AGN-209323, a Phase II, orally administered small molecule for neuropathic pain, through a potential novel undisclosed mechanism of action. AGN-209323 was discovered as part of collaboration between Allergan and ExonHit Therapeutics SA.

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Critical illness myopathy (CIM) or critical illness polyneuropathy (CIP): bad sign!

German anesthesiologists and neurologists analysed whether there is an association between the early differentiation ofcritical illness myopathy (CIM) versus critical illness polyneuropathy (CIP) and clinical prognosis. 

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Low Doses of Palmitoylethanolamide: a selective GPR55 agonist

GPR55 receptor is highly expressed in large dorsal root ganglion neurons of spinal cord.

Several mechanisms have been suggested for the antinociceptive and anti-inflammatory actions of PEA. The relative contribution of cannabinoid CB1, vanilloid and PPARγ to PEA-induced antinociception effects has been shown in previous studies. 

The antinociceptive effect of PEA as a selective GPR55 agonist/weak cannabinoid receptor agonist was studied in a rat model. Based on the results the authors suggested that GPR55 receptors are involved in pain modulation and could be considered as an important target for antinociceptive therapies. 

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Horizant, gabapentin enacarbil, not yet on the market

In  February 2010 gabapentin enacarbil for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) was not receiving approval by the FDA due to concerns regarding findings of pancreatic acinar cell tumors in rats.

Horizant, is a prodrug of Pfizer’s gabapentin. 

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Calmare(R) Pain Therapy Treatment in neuropathy proceeds

Calmare(R) Pain Therapy Treatment in neuropathy proceeds, as they raised new capital to provide financing for CTT to more aggressively sell its innovative Calmare(R) Pain Therapy Treatment, which treats chronic neuropathic and oncologic pain, both in the U.S. and internationally. The CEO John B. Nano remarked:

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R-flurbiprofen reduces glutamate in neuropathic pain

R-flurbiprofen, an enantiomer of flurbiprofen racemate, is inactive with respect to cyclooxygenase (COX) inhibition, but in vivo it shows analgesic properties. Its mechanism of analgesic action is unknown, but R-flurbiprofen reduced glutamate release in the dorsal horn of the spinal cord evoked in a sciatic nerve injury models of neuropathic pain.

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Palmitoylethanolamide protects mitochondria against toxic stress

Palmitoyethanolamide (PEA) is a remarkable lipid. In 1973 HANA OBERMAJEROV and colleagues from the Institute of Pharmacology, Czechoslovak Academy of Sciences, published a paper were they discussed a number of experiments, using mitochondria, stressed by different toxins, were they detected a protective effect of PEA.

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Channelopathies: increasing understanding

Inherited mutaions of ion channels can affect central and peripheral nervous system. Most of these chanches in the fundtion of ionchannels influence the function of brain, spinal cord, peripheral nerves or muscles. The disturbances are not continous, but intermittent.

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Topical low dose clonidine gel to treat Diabetic Neuropathy: phase 2 results

A phase 2b double-blind, randomized, placebo-controlled clinical trial, involving topical gel candidate ARC-4558 for the treatment of painful diabetic neuropathy produced effective results in relieving the pain, according to a press release of the company in july 2010.

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Metabolism and degradation of palmitoylethanolamide

Metabolism and degradation of palmitoylethanolamide, a short analysis of a special therapeutic enodcannabinoid.

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ARC-4558, transdermal clonidine gel for neuropathic pain

ARC-4558 is the code for a transdermal gel in  development for the treatment of neuropathic pain. The gel is being developed by Arcion Therapeutics, Inc. and the company received in february 2010 $8 million to further develop this innovative gel. Arcion is a socalled venture backed clinical biotechnology company, focussing on pain treatment.  

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GRC 15300, a Vanilloid (TRPV)3 antagonist for neuropathic pain

Glenmark Pharmaceuticals Ltd. (GPL) announced in 2009 that its candidate for Neuropathic pain, GRC 15300 has been filed for Phase I trials. GRC 15300 is descibed as a Transient Receptor Potential Vanilloid (TRPV)3 Antagonist.

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PEA: Evolution in pharmacological thinking: palmitoylethanolamide

palmitoylethanolamide.jpg The rising of concepts in pharmacology is a highly interesting topic. The discovery of the Cannabis receptors and the nuclear PPAR receptors have been the base of a total new understanding of may important homeostatic physiological medhanisms in our body. [1] These discoveries were necessary for us to understand the analgesic and anti-inflammatory activity of the body-own fatty amide palmitoylethanolamide. This molecule was identified as an important modulator during tissue stress as in chronic inflammation and pain and during tissue disttruction such as in ischemia. Palmitoylethanolamide (PEA) is a foordcomponent known already for more than 50 years. PEA is also a molecule widely present in animals and mammals, only it cannot be found in insects. Palmitoylethanolamide is synthetized and metabolized in animal cells via a number of enzymes and it excerts a multitude of physiological functions, related to metabolic homestasis. PEA and has been identified already in the 50s of last century as a therapeutical principle with potent anti-inflammatory properties.  Since 1975 its analgesic properties were noticed and explored in a variety of painstates. Since 2008 palmitoylethanolamide (PEA) is available as dietfood for medical purposes in countries in Europe (Italy, Spain, Germany) under the brandname Normast, produced by the Italian company Epitech. Currently palmitoylethanolamide is evaluated as special diet-treatment for Inflammatory Bowel Syndrome under te brandname Recoclix by CM&D Pharma Ltd and Nestlé. Since 2012 palmitoylethanolamide is also available under the brandname PeaPure, produced by the company Russell Science Ltd. More info in PEA under this link The history of palmitoylethanolamidel started in 1954 with a publication addressing the anti-inflammatory properties of egg yolk (see figure 1). Findings that egg yolk appeared to be some sort of ‘medical diet-food avant la lettre’ and the fact that extracts from egg yolk and peanut oil possessed anti-inflammatory activities, were discussed in that paper. Research on PEA has been conducted for more than 50 years and over 300 papers are referenced in Pubmed, describing the physiological properties of this endogenous modulator and its pharmacological and therapeutical profile. The history of the emergence of insights in the biological roles this molecule might play after its identification in 1957 is worth telling. It demonstrates the close interrelation between the scientific contex and the development of scientific facts. It also shows that plausible explanations of the mechanism of action of drugs are required before a treatment concept will be explored in more detail in science and in the clinic. Without a satisfactory explanary concept, efficacy of a compound alone will not be enough to convince the scientific community. The case of PEA demonstrates this scientific sociological finding, and PEA research sunk in oblivion in the period were no mechanism of action was convincingly demonstrated.

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Neuronal damage leads to increase production palmitoylethanolamide and other endocannabinoids

Neuronal damage as assessed by transection of long-range projections apparently provides a strong time-dependent and area-confined signal for de novo synthesis of various endocannabinoids, presumably to restrict neuronal damage. In an elegant study Sonja Kallendrusch and colleagues pointed out some recent studies demonstrating the neuroprotective properties of endocannabinoids in various models of neuronal lesion in vitro and in vivo. Palmitoylethanolamide, they emphesised, mediates its neuroprotective effects via dual PPAR alpha activation on microglial cells and neurons.

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Pfizer working on new leads in neuropathic pain

Pfizer is working on consolidating its pipeline in pain, based on some new leads and other steps to strenghten their position in the market of neuropathic pain. They are working on compounds and innovations for: 

  1. Peripheral neuropathic pain
  2. Central neuropathic pain
  3. Post-operative pain
And on combination therapy for pain: Combo therapy with PF-4880682. Furthermore they are looking into new α2δ Ligands to ‘Expand a Successful Class of Drugs’

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MDA19: pharmacological profile of cannabinoid ligand

The cannabinoid receptor 2 (CB(2)) agonists are potential therapeutic targets in the treatment of neuropathic pain. The pharmacological profile of  N’-[(3Z)-1-(1-hexyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide (MDA19), a CB(2) agonist suggest MDA19 could be a analgesic for the treatment of neuropathic pain.

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