Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action

Hesselink, Jan M Keppel; Kopsky, David J

doi:10.1007/s00415-017-8391-5

Cited by 52 publications

(38 citation statements)

References 36 publications

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“…21,54 This fact could be explained by differences in the selectivity and the pharmacokinetics profile of both compounds. 52 Our results provide us the opportunity for further structural optimization based on the interactions with Nav1.2 proposed by molecular modeling. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24 4.1.1 Construction of Nav1.2.…”

Section: Discussionmentioning

confidence: 76%

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents

Palestro

Enrique

Goicoechea

et al. 2018

J. Chem. Inf. Model.

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The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.

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Section: Discussionmentioning

confidence: 76%

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents

Palestro

Enrique

Goicoechea

et al. 2018

J. Chem. Inf. Model.

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“…Although many patients were responders to compounded creams containing for example amitriptyline, ketamine, and baclofen, a number of patients remained treatment-resistant. We therefore introduced phenytoin as a new compound for topical neuropathic pain treatment based on its remarkable history and its various modes of action [ 15 , 16 , 17 ]. Phenytoin, as a broad-acting ion channel blocker with neuroprotective and anti-inflammatory properties, seemed to be an optimal choice as an effective compound that is able to modulate peripheral mechanisms, which are increasingly recognized as important drivers in neuropathic pain [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Phenytoin Cream for the Treatment of Neuropathic Pain: Case Series

Kopsky¹,

Hesselink²

2018

Pharmaceuticals

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BACKGROUND: Neuropathic pain can be disabling, and is often difficult to treat. Within a year, over half of all patients stop taking their prescribed neuropathic pain medication, which is most probably due to side effects or disappointing analgesic results. Therefore, new therapies are needed to alleviate neuropathic pain. As such, topical analgesics could be a new inroad in the treatment of neuropathic pain. In 2014, we developed a new topical formulation containing either phenytoin or sodium phenytoin. After optimization of the formulation, we were able to reach a 10% concentration and combine phenytoin with other co-analgesics in the same base cream. OBJECTIVE: To describe a series of 70 neuropathic pain patients who were treated with phenytoin cream. MATERIAL AND METHODS: Cases treated with phenytoin 5% or 10% creams were gathered. The mean onset of pain relief, the duration of effect, and reduction in pain intensity measured on the 11-point numerical rating scale (NRS) were all studied. A single-blind response test with phenytoin 10% and placebo creams was conducted on 12 patients in order to select responders prior to prescribing the active cream. Plasma phenytoin concentrations were measured in 16 patients. RESULTS: Nine patients applied phenytoin 5% cream, and 61 patients used phenytoin 10% cream. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 min (SD: 14.8), the mean duration of analgesia was 8.1 h (SD: 9.1), and the mean pain reduction on the NRS was 61.2% (SD: 25.0). The mean pain reduction on the NRS while using phenytoin cream was statistically significant compared with the baseline, with a reduction of 4.5 (CI: 4.0 to 5.0, p < 0.01). The 12 patients on whom a single-blind response test was performed experienced a statistically significant reduction in pain in the area where the phenytoin 10% cream was applied in comparison to the area where the placebo cream was applied (p < 0.01). Thirty minutes after the test application, the mean pain reduction on the NRS in the areas where the phenytoin 10% cream and the placebo cream were applied was 3.3 (CI: 2.3 to 4.4, p < 0.01) and 1.1 (CI: 0.4 to 1.9, p < 0.05), respectively. In all 16 patients, the phenytoin plasma levels were below the limit of detection. So far, no systemic side effects were reported. Two patients only reported local side effects: a transient burning aggravation and skin rash. CONCLUSION: In this case series, the phenytoin cream had reduced neuropathic pain considerably, with a fast onset of analgesic effect.

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“…(Figure 3) [51]. we also found that phenytoin can augment the analgesic effects of other (co-)analgesics [52].…”

Section: Phenytoin Cream Formulation Repositioning Strategymentioning

confidence: 54%

Amantadine and phenytoin: patent protected cases of drug repositioning

Hesselink¹

2017

Clinical-Investigation

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Repositioning of old drugs in new indications is a hot topic. However, there are some hurdles to take, and one is related to financial attractiveness. We will discuss two examples to solve this problem based on patents: phenytoin cream for neuropathic pain and amantadine extended release for dyskinesia and other neurological disorders, and discuss amantadine, its history of repositioning and its patents in more detail. Both molecules are respectable old compounds, phenytoin was synthesized more than a century ago, and amantadine in the 50s of last century.Amantadine was first recognized as an antiviral compound in the 60s of last century, and was approved by the FDA for flu prophylaxes in 1966. Parkinson was its first repositioning indication, triggered by a case study in 1968. Subsequently a great variety of indications were explored, from fatigue in multiple sclerosis, enuresis nocturna, ADHD, up to pathological gambling and recovery after head injury. Amantadine is currently developed as an extended release formulation for levodopa-induced dyskinesia in Parkinson's disease (preapproval phase). It is protected by a patent from 2009, claiming a special formulation and time of intake.While its antiviral mechanism of action has been clarified, the mechanisms of action in other indications are still quite enigmatic. At the end of last century, it was stipulated that amantadine and comparable drugs with unexplained mechanisms may deserve additional studies to enfold its full therapeutic potential. Based on an analysis of the clinical perspectives for amantadine at that time it was felt necessary to developing an infrastructure for funding research on new purposes for older drugs after they lose patent protection. Nearly 2 decades later such recommendation still remains valid.

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Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action

Cited by 52 publications

References 36 publications

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents

Phenytoin Cream for the Treatment of Neuropathic Pain: Case Series

Amantadine and phenytoin: patent protected cases of drug repositioning

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