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Research & Development

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

CR845 (Difelikefalin), A Kappa Receptors Agonist In Phase III By CARA Therapeutics

CR845: (difelikefalin), a peripheral opioid agonist currently developed by Cara Therapeutics, an analysis.

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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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Flupirtine from CNSBio in neuropathic pain

Flupirtine from CNSBio is in phase I for the development in neuropathic pain. However, flupirtine is an old molecule, aminopyridine. It has been used as an analgesic in the past and is still on the market in various countries.

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Cannabinoids and nerve regeneration or neurogenesis

Most people and neurologist view nerves as ‘copper ropes’ conducting electricity. If the copper rope breaks, the nerve is damaged, and the damage is for the rest of our life. This creates great nihilism for therapeutic innovations. And even more disturbing, patients feel this metaphore is a desription of reality. The message patients often get from their neurologist is: nothing can be done, what is dead remains dead….

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Painkillers efficacy in 2010 less compared to 2005

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TRO19622, Olesoxime in painful neuropathy

TRO19622 is the code name for the substance olesoxime currently being studied for painful neuropathy. It is a cholesterol-like substance that is designed to be a treatment of a serious disease, such as amyotrophic lateral sclerosis. Animal studies showed the neuroprotective activity, based on the its mechanism of action within the nerve cell.Trophos SA,is developing therapeutics from discovery to clinical validation for indications with under-served needs in neurology and cardiology.Olesoxime is tested in an ongoing pivotal efficacy study in amyotrophic lateral sclerosis, snd efficacy results are expected in 2011.

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Melatonin: protective in chemotherapy for neuropathy?

Melatonin demonstrated neuroprotective effects in a variety of animal studies and has been suggested to decrease adverse reactions of chemotherapy including neuropathy. In a pilot trial melatonin, 21 mg before sleep, given during taxane chemotherapy for breast cancer, decreased the incidence and severity of neuropathy.

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Migraine and mast cells

mast_cell_jmkh.gifThe pathophysiology of migraine is complicated. Since some years a new dimension has opened, based on our insight in the behaviour of the mast cell in meningen. Migraine occur in nearly 1 in 5 adults in the US, are migraine attacks precipitated by stress, and are also associated with high disability, medical and economical costs and loss of quality of life. There are more than 74 million migraine patients in the US, France, Germany, Italy, Spain, and the UK in 2002 and the migraine drug market estimated at $2.86 billion in 2002 expecting to double by 2012….

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Montalcini on PEA protection

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PH-797804 in neuropathic pain: a Novel N-Phenyl Pyridinone Inhibitor of p38 MAP

A proof-of-concept study to determine if PH-797804 reduces neuropathic pain associated with post-herpetic neuralgia is under way (2010). Patients will be randomized to receive either PH-797804 or placebo for 4 weeks, during which time they will also record their pain symptoms using various pain scales. PH-797804 is a compound from Pfizer. 

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Radiprodil fails in diabetic neuropathy

radiprodil.gifForest Laboratories reported that its new drug for neuropathic pain, radiprodil, had failed to achieve its objectives in stage 2 clinical trials. The medicine was developed in partnership with Hungarian drug maker Gedeon Richter, Ltd. It had been hoped that it would be useful for patients with peripheral neuropathy resulting from diabetes.

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Selected pharmacology of palmitoylethanolamide

The discovery of our own ‘Cannabis", the molecule anandamide, as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides.  N-palmitoylethanolamine (PEA) is a sistermolecule of anandamide, a shorter and fully saturated analogue, and this molecule has been known since the fifties. In the sixties and seventies much research supported its use as prophylactic treatment for the flu, and the compound was on the market available as Impulsin.

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JNJ 42160443 from Johnson in neuropathic pain

JNJ 42160443 from Johnson in neuropathic pain, phase II. Hereunder the update of clinical trials running for this compound, as of April 2010. The Janssen compound is a monoclonal antibody directed against nerve growth factor (NGF). In animal models it demonstrates potential analgesic activity. Anti-nerve growth factor monoclonal antibody JNJ-42160443 binds to NGF, and prevents its binding to the NGF receptors TrkA and p75NTR. Inhibition of this pathway may prevent neuropathic pain.

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AstraZeneca and neuropathic pain

AstraZeneca, a pharmaceutical company, has three compounds in clinical development for neuropathic pain:

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Natrium channel disruption in small fibre neuropathy

The Na(V)1.7 sodium channel can be found in the dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. The so called ‘gain-of-function’ variants of the Na(V)1.7 channel have recently been described in patients with painful small fibre neuropathy.

It is probably that a novel syndrome of pain, dysautonomia, small hands and small feet can be understood from a novel Na(V)1.7 mutation.

A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). 

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The development of new analgesics over the past 50 years: a lack of real breakthrough drugs.

The development of new analgesics over the past 50 years: a lack of real breakthrough drugs.

Quite a provocative titel! A single author article in one of the leading journals for anesthesiologists specailizing in the treatment of pain. What does the author exactly say?

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Why do so many drugs fail in phase II?

In the internet there is a big community of specialists involved in drug R&D and at LinkedIn there are quite some interesting discussions related to topics worth while considering. The question which haunts many drug developers is: Why is it that so many drugs flunk after phase II trials? That question is also immensly important for the development of drugs in the field of chronic pain. But it is a generic question. 

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NeurogesX to Qutenza® (capsaicin) 8% Patch in HIV-Associated Neuropathy

In a recent press release (18-10-2010) it was communicated that the company NeurogesX  U.S.will try to broaden the indications for Qutenza® (capsaicin) 8% patch to include patients with painful HIV-associated neuropathy (HIV-AN, also referred to as HIV-distal sensory polyneuropathy (HIV-DSP)). Following a recent meeting with the U.S. Food and Drug Administration (FDA), NeurogesX plans to submit a supplemental new drug application (sNDA) in the first half of 2011.

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NGF can be counteracted: green light for NGF antibodies

A Advisory Panel Gives the Green Light to Restart NGF Antibody Trials
Investigators pleased that promising agents for pain relief have new life, states a new entry in http://www.painresearchforum.org. Interestingly palmitoylethanolamide with which we work is a natural inhibitor of the effects of NGF!

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iNOS inhibitor KD7040 topical for neuropathic pain

In our clinicl we have good results using a topical cream based on ISDN, isosorbine dinitrate, a NOS inhibitor. The company Kalypsys is currently developing molecules targeting iNOS, a member of the nitric oxide synthase (NOS) family of enzymes.

Nitric oxide (NO) in the skin has been implicated in the pathophysiology of pain and inflammation.The lead molecule in this area of Kalypsys is is KD7040, a potent, topically administered, inhibitor of iNOS.

 

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Zinc vinger binding SB-509 in diabetic neuropathy: positive phase II

On juli 1st 2010 Sangamo BioSciences announced positive Phase 2 data from its program to develop SB-509 as a treatment for diabetic neuropathy (DN). The data was gathered from Sangamo’s phase II trials that demonstrated that SB-509 treatment resulted in clinically improvements in subjects with moderate and severe DN as compared to placebo. SB-509 is an injectable plasmid encoding a DNA-binding zinc finger DNA-binding protein (ZFP) transcription factor (ZFP TF). It is designed to upregulate the endogenous expression of the gene encoding vascular endothelial growth factor (VEGF-A). VEGF-A has been demonstrated to have direct angiogenic, neurotrophic and neuroprotective properties.

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Mast cells , periapical inflammation, peridontitis and palmitoylethanolamide

Among the cells involved in immune and inflammatory responses in periodontal disease, mast cells seem to play a major role. This is important as mast cell hyperactivity can be inhibited by the natural compound palmitoylethanolamide.

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Taurine for painful diabetic neuropathy

taurine.jpegTaurine 3,000 mg/day (3 capsules) orally vs placebo 3 capsules daily for 12 weeks is evaluated currently in a RCT in the UK. The idea of the trial is that taurine depletion contributes to the development of painful Diabetic Neuropathy (DN). This rationale is based on:  

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KRN5500 Kirin Brewery and Massachusetts General Hospital, DARA Biosciences

KRN5500 Kirin Brewery and Massachusetts General Hospital, is licenced to DARA Biosciences, and currently in phase II for neuropathic pain. KRN5500 (6-[4-Deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-ß-L-manno-heptopyranosyl]amino-9H-purine) has been targeted for specific indications: Neuropathic Pain in cancer patients, in particular, chemotherapy-induced peripheral neuropathy (CIPN). KRN5500 is a novel non-opioid analgesic agent, a semi-synthetic derivative of spicamycin.

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Axonal regeneration: the ‘signaling endosome’ model

Distal axonal degeneration is a hallmark of many neuropathies. Traditionally we tended to think in a simpel degeneration-regeneration model. The celbody of each neuron, based on the functions of its residing nucleus, is key in regeneration, and all regeneration processes are anterograde. Failure of metabolic support for the cellbody causes an impairement in the function of the axon, due to the fact that the axon itself is poorly inhabited by ribosomes and mitochondia and thus the axon is totally dependent on support from its master, the cellbody. In 1997 Spencer at all described the degeneration proces using an analogy of the farthest meaddow, which is the first to be drowned from water support, if the waterpump fails. These analogies and metaphors always play a big role in our understanding and our apporach of scientific problems and clinical problems.     

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