Phentytoin cream finds its way into state of the art review

Phentytoin cream finds its way into state of the art review

In the authorative Journal ‘Expert Opinion on Pharmacotherapy’, Prof. Terence J. Coderre wrote an impressive overview on topical drug therapy for neuropathic pain.

Dr. Coderre is a Harold Griffith Professor in Anesthesia Research at McGill University. He is also the director of pain research laboratories in the Anesthesia Research Unit and at the MUHC Research Institute, and a member of the McGill Centre for Research on Pain.

His expert opinion is that current topical therapeutics for neuropathic pain rely too heavily on the use of local anesthetics and capsaicinoids. He pleads for more research on topical therapies that are multimodal and/or are targeted at the peripheral sources of pathology.

Our phenytoin cream was also referred to in his review, and he mentioned topical 5–10% phenytoin pointing out that it has recently been found to be effective at reducing NP in a case series of 70 patients. He also pointed out the relevance of combinations, such as phenytoin + baclofen or ketamine and other multi-drug combinations.

This is an important milestone in the start of our phenytoin project, to be referred to in an important up-to-date review.

Reference

Terence J. Coderre (2018): Topical drug therapeutics for neuropathic pain, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2018.1501026

Phenytoin Topical Project ready to enter phase III after meeting with the Dutch Medicines Evaluation Board

Phenytoin Topical Project ready to enter phase III after meeting with the Dutch Medicines Evaluation Board

In June 2018, a so called Tailored Advice Procedure at the Dutch Medicines Evaluation Board was initiated regarded the next developments steps of topical phenytoin cream. The aim of such development is to obtain registration for topical phenytoin cream in Painful Diabetic Neuropathy.

This tailor-made advice is customized advice mainly aimed at start-ups, small businesses and academic groups. In general, the advice will primarily relate to the early stage of development (pharmaceutical or pre-clinical aspects, phase I clinical research), although in the case of topical phenytoin cream the project was also eligible at a later stage (before entering phase III). Drug Rediscovery is frequently a topic; this involves the development and registration of a new application of an existing medicine, as in the phenytoin case. During such advice, questions can be asked about the ‘regulatory road map’, for example towards Europe.

Such meetings are primarily intended to advance, in an informal setting, to an effective exchange of (scientific) insights and gives both the applicant and the experts of the Dutch MEB the opportunity to ask for specific aspects or to provide further explanation.

The input given by the Dutch agency will be instrumental for the development of a crisp and clear phase III development, for which preparations currently are already underway. First discussions related to phase III are held at one of the Academic hospitals in Amsterdam.

Due to these developments TI started to look seriously for partners on either a local or global base. The partner would take up the last development step and become responsible for registration, marketing and sales. Further information: info@topicalinnovations.com

Nociceptors in neuropathic pain and Nav1.7 channels: new insights

Nociceptors in neuropathic pain and Nav1.7 channels: new insights

Pseudo-unipolar neurons of the dorsal root ganglion have one axon that is divided into two separate branches, one leads impulses from the periphery to the cell body in the ganglion, and one carrying impulses from the body to the spinal cord. These cells start in the periphery. Nociceptors in the peripheral nervous system are these pseudo-unipolar dorsal root ganglion neurons and they possess either unmyelinated or thinly myelinated axons, and are thus responsible for the emergence of pain in neuropathic pain.

Peripheral voltage-gated sodium channels, including Nav1.7, are mainly expressed in the DRG cells, and are seen to be central for understanding the mechanism behind neuropathic pain.

In a recent study the pain behavior and the expression of the Nav1.7 channels in the DGR were studied before and after plantar incision in rats. This can be seen as an acute postoperative pain model.  After the operation, mechanical and thermal pain threshold decreased significantly, the cumulative pain score was increased significantly. Expression of Nav1.7 in the DGR cells was enhanced significantly, and pain behavior could be inhibited by Scn9a Antibodies.

The enhanced expression of sodium channels in the peripheral nerve cells which act as nociceptors support the further development of phenytoin local cream, which inhibits these Nav1.7 channels as well as other sodium channels.

 

Source: Sun J, Li N, Duan G, Liu Y, Guo S, Wang C, Zhu C, Zhang X. Increased Nav1.7 expression in the dorsal root ganglion contributes to pain hypersensitivity after plantar incision in rats. Mol Pain. 2018 Jan 1:1744806918782323. doi: 10.1177/1744806918782323.

Topical Analgesia Information welcomed at 3rd Eastern-European Pain Congress: 7−9 June 2018, Kiev, Ukraine

Topical Analgesia Information welcomed at 3rd Eastern-European Pain Congress: 7−9 June 2018, Kiev, Ukraine

The topic ‘topical analgesics’ was hot during the at 3rd Eastern-European Pain Congress 2018, in Kiev, Ukraine. On 2 days (7th and 8th June) topics related to topical analgesia were presented, amongst others by Dr Roberto Casale, who focused on lidocaine plaster experiences and mechanisms of action, by Prof. dr. Jan M. Keppel Hesselink who presented a review on the use of topical ketamine, baclofen, clonidine, amitriptyline and phenytoin based on the 8 years’ experience gathered at the Institute for Neuropathic Pain and by David Kopsky, MD, who presented the innovative single and double blind cross-over n=1 response tests. One of the leading pain physicians from Germany made a remark that topical analgesia making use of repositioned drugs such as phenytoin is the best news in the field of chronic pain treatment since the introduction of pregabalin. During the discussions, many attentive colleagues asked specific questions on the practicalities of the use of the creams, and clearly it was pointed out that there is a great need for such innovations, the more so as there are only few new approaches without troublesome adverse events.

9th International Conference on Clinical & Medical Case Reports: Keynote speech on n-of-1 case collections based on phenytoin cream in painful neuropathy

9th International Conference on Clinical & Medical Case Reports: Keynote speech on n-of-1 case collections based on phenytoin cream in painful neuropathy

At the 9th International Conference on Clinical & Medical Case Reports September 27-28, 2018 at Amsterdam, the Netherlands the focus is:

Role of Clinical & Medical Case Reports in redefining the Healthcare system

One of the TI founders, David Kopsky, will present the key note speech on the development of phenytoin as a topical treatment for localized peripheral neuropathic pain. See link

He will discuss how n-of-1 studies can be conducted in the clinical practice, including the use of a placebo, in order to identify responders from non-responders and thus design a personalized therapy.

Physicians of TI present phenytoin at 3rd Eastern-European Pain Congress: 7−9 June 2018, Kiev, Ukraine

Physicians of TI present phenytoin at 3rd Eastern-European Pain Congress: 7−9 June 2018, Kiev, Ukraine

It is to be expected that the 3rd East-European Pain Congress will become quite a big pain-related meeting in Eastern Europe. The theme of the 2018 Global Year for Excellence in Pain Education is “Bridging the gap between knowledge and practice.” It is in this context that Professor Keppel Hesselink, MD and David Kopsky, MD will be amongst the key speakers and present a number of latest findings related to the project of repurposing phenytoin as a cream for the treatment of peripheral neuropathic pain.

Currently planned is one plenary session on June 8th presenting a general overview of the topic: ‘new developments in topical treatment of peripheral neuropathic pain from the perspective of repositioned drugs’

During the topical symposium on June 8th, dedicated to the more general topic: ‘topical treatment in peripheral neuropathic pain’ David tentatively will discuss: ‘enrichment designs in topical analgesic treatment, the role of a single blind response test in research and daily practice’. Jan will present: ‘the role of topical phenytoin formulations in the treatment of peripheral neuropathic pain.’

Phenytoin: a new cytoprotective mechanism

Phenytoin: a new cytoprotective mechanism

An impressive group of scientists from Germany, Spain, USA and France worked on discovering a new cellular mechanism of phenytoin, a mechanism leading to cellular protection [1]. They published the results in March 2018. We have described phenytoin’s protective mechanism on the level of nerve cells before [2,3], but these researchers found a new key for the necroptosis inhibition of phenytoin.

They stipulate that based on their findings phenytoin could be repositioned in kidney ischemia-reperfusion injury (IRI), and phenytoin also appeared to protect cells from TNFα-induced severe inflammatory response syndrome (SIRS).

Via a series of elegant experiments they found out that phenytoin amongst other mechanisms prevents necrosome formation and partially inhibits RIP1 kinase. Necroptosis is the best studied pathway of regulated necrosis and is mediated by receptor-interacting protein kinases 1 and 3 (RIPK1/3). The exact mechanism of phenytoin is still unclear, but it is NF-kB signaling independent.

Their conclusion highligts a new putative indication for phenytoin: With greater than 60 years of clinical experience and low costs alongside with the availability on ICUs and in ambulances, phenytoin may provide a drug to target necroptosis.

Given our own findings we think this mechanism might be related to its analgesic effects in small fiber neuropathic pain.

Sources

    1. von Mässenhausen A, Tonnus W, Himmerkus N, Parmentier S, Saleh D, Rodriguez D, Ousingsawat J, Ang RL, Weinberg JM, Sanz AB, Ortiz A, Zierleyn A, Becker JU, Baratte B, Desban N, Bach S, Schiessl IM, Nogusa S, Balachandran S, Anders HJ, Ting AT, Bleich M, Degterev A, Kunzelmann K, Bornstein SR, Green DR, Hugo C, Linkermann A. Phenytoin inhibits necroptosis. Cell Death Dis. 2018 Mar 2;9(3):359. doi: 10.1038/s41419-018-0394-3.
    2. Keppel Hesselink JM, Kopsky DJ. Phenytoin: neuroprotection or neurotoxicity? Neurol Sci. 2017 Jun;38(6):1137-1141. doi: 10.1007/s10072-017-2993-7.
    3. Chiosi F, Keppel Hesselink J, Rinaldi M, Di Staso S, Bartollino S, Costagliola C. Phenytoin: its potential as neuroprotective and retinoprotective drug. Br J Clin Pharmacol. 2018 Jan;84(1):195-196. doi: 10.1111/bcp.13435.

Phenytoin reverses chemotherapeutic hair and skin damage

Phenytoin reverses chemotherapeutic hair and skin damage

Chemotherapy against cancer does not only lead to neuropathy and neuropathic pain, it also leads to hair loss:chemotherapy-induced alopecia (CIA). Recent animal models of CIA have been used to document the changes in the morphology of hair follicles after chemotherapy. These models can also assist in analyzing the effects of potential topical or systemic therapeutic agents in the prevention or amelioration of alopecia. The efficacy of certain drugs in animal models of CIA have been studied, among others antioxidants, apoptosis-inhibitors, growth factors and cytokines.

Phenytoin is known to induce unwanted hair growth, as one of their side-effects, and in dermatology, phenytoin has been used in the treatment of ulcers associated with diabetes and epidermolysis bullosa. In this recent study the effect of phenytoin on alopecia in cyclophosphamide-treated rats versus placebo was studied. The hypothesis was tested that the administration of phenytoin may significantly suppress hair loss in cyclophosphamide-treated rats.

Treatment with phenytoin led to increased body weight, reversal of cyclophosphamide induced lipid peroxidation/oxidative stress, improved hair growth, and reduction in cyclophosphamide induced dystrophic changes in the skin.

Phenytoin also led to an increase in the number of follicles. In the past topical application of phenytoin was found to stimulate proliferation of fibroblast, formation of granulation tissue, tolerance of tissue elasticity, inhibition of glucocorticoid production and growth of hair follicles. The stimulation of growth of hair follicles is a beneficial effect counteracting chemotherapy-induced hair loss; and in this study, growth of hair follicles following administration of phenytoin was found. Additional results obtained suggested that oral phenytoin was associated with other systemic benefits such as amelioration of oxidative stress.

Source: A.Y Onaolapo, et al., Oral phenytoin protects against experimental cyclophosphamide-chemotherapy induced hair loss. Pathophysiology, 2017

New drugs for Neuropathic Pain badly needed!

New drugs for Neuropathic Pain badly needed!

In Pain Medicine News of 2017 an analysis is presented of many recent meta-analysis and studies to evaluate our current painkillers in neuropathic pain. The result is actually shocking, as we need to conclude that in this field not much progress exists, and old drugs are only borderline effective. The title of the analysis is telling: ‘Evidence Lacking for Current Pharmacologic Treatment of Neuropathic Pain’

We quote from this important review: “When we examine the published recommendations on neuropathic pain, we end up with a consensus statement without a strong evidentiary basis,” according to one of the reviewers, Dr. Rosenquist. He also states: “Further guidance regarding appropriate patient selection and drug and dose strategies is needed to improve management with current drugs. If we’re really going to make a difference for our patients going forward, new drug development to treat these conditions with greater reliability and a smaller side-effect profile is urgently needed.”

This is exactly the field in which Topical Innovations is working. Exploring individualized medicine in the field of neuropathic pain and developing tailor-made solutions for patients based on topical formulations of the unique compound and painkiller phenytoin.

 

Topical analgesics can reduce opioid use

Topical analgesics can reduce opioid use

Chronic, noncancer pain, among which neuropathic pain affects around 200 million people in Europe and the USA and is one of the most frequent reasons for patients to visit their primary care physician. Patients experiencing chronic pain often also have multiple other disorders and take many drugs. Unfortunately, most analgesics, such as antiepileptics, antidepressants, opioids and NSAIDs, are associated with adverse events and drug-drug interactions and tolerability issues reduce compliance and efficacy. Topical and transdermal analgesic formulations have many advantages for patients, especially for the elderly, and combine efficacy with absent or low systemic levels of drug.

The Optimizing Patient Experience and Response to Topical Analgesics (OPERA) study is an observational survey study of patients who experience chronic neuropathic or other pain and who have been prescribed a topical or transdermal analgesic formulation in various combinations, such as based on diclofenac, ketoprofen, amitriptyline, gabapentin, bupivacaine or other pain-relieving transdermal cream.

A total of more than 400 patients had been prescribed some form of topical analgesic formulation, including:

  • Flurbiprofen (20%)
  • Amitriptyline (5%)
  • Magnesium Chloride (10%)
  • Gabapentin (6%)
  • Bupivicaine (2%)

Results

The Overall Brief Pain Inventory (BPI) scores showed major improvements, where overall severity scores decreased significantly by 31.3% (P< 0.001). Specifically, all 4 components of the BPI Severity score showed clear improvements.

Especially important was the fact that topical analgesics can reduce the intake of painkillers such as opioids and NSAIDs.

Topical Innovations is dedicated to find more topical analgesic formulations to improve quality of life of pain patients and reduce pain in neuropathic pain states.

Reference

Gudin J, Brennan M, Harris E, et al. Decreased pain following use of a topical analgesic: Interim results from the Optimizing Patient Experience and Response to Topical Analgesics (OPERA) observational study. Poster presentation at: 8th Annual Meeting of the World Institute of Pain; May 20-23, 2016; New York, NY.