TOPICAL DELIVERY - Direct Effects™ Perampanel (FYCOMPA®): First Topical Anticonvulsant to Treat Seizures, Headache & Other Symptoms in Epilepsy

INTRODUCTION

Seizures are the hallmark manifestation of a pathologically heightened excitable state within the central nervous system (CNS). However, other symptoms of brain hyper-excitability may coexist. These may consist of various forms of head pain, difficulty thinking and concentrating, inattention, memory problems, and mood changes such as depression, anxiety, agitation, impulsivity, social isolation, and fatigue. These additional symptoms impact quality of life and can exist in the absence of overt seizures; often occurring on a regular and persistent basis.¹

We studied 106 patients at an outpatient neurology practice with epilepsy and varied other conditions indicative of brain hyper-excitability. We sought to see what effect the anticonvulsant perampanel, FYCOMPA^®, may have on symptoms when used in topical form with the Direct Effects™ non-systemic technology.

FYCOMPA is an anticonvulsant in oral tablet and suspension forms which acts as a glutamate AMPA non-competitive receptor antagonist. It is approved to treat partial-onset seizures in patients 4 years and older. AMPA receptors are critical for me­diating glutamatergic excitatory synaptic transmission.²

Glutamate, as a primary excitatory and the most abundant neurotransmitter in CNS, is implicated in the initiation of mi­graine and central sensitization. Evidence suggests glutamate and its receptors are intimately involved in migraine pathophys­iology. AMPA, NMDA, and kainate exist as glutamate receptor subtypes.

Migraine involves alteration in the ex­citability of multiple regions of CNS; par­ticularly the Trigeminal Nerve Complex, the “Headache Center.” Accordingly, through diverse effects, glutamate plays a crucial role in migraine pathophysiology.³

There is also strong evidence impli­cating disturbances in glutamate metabo­lism and its receptors playing an important role in depression. It has been determined that many of the traditional pharmacolog­ical agents for depression and mood dis­orders ultimately affect the glutamate system. Hence, newer drugs that specifi­cally target glutamate from the outset are now being introduced. The ketamine nasal spray esketamine, Spravato^® and Auvelity^®, the combination of bupropion and dextromethorphan are examples. The Auvelity is thought to specifically treat an­hedonia. Anhedonia is the condition in which one is not particularly depressed; but, derives no pleasure in life. Excessive glutamate in CNS is associated with the hyper-alert states that accompany PTSD, anxiety and panic attacks. Abnormally high levels of glutamate are also found in head trauma, autism spectrum disorder, and chronic pain states.⁴

We previously reported on topical ke­tamine treating migraine and neuropathic pain; in addition to being of benefit in PTSD and intractable depression.^4,5 Keta­mine is a glutamate NMDA receptor an­tagonist. Both ketamine and FYCOMPA are designated Schedule III controlled sub­stances by the Drug Enforcement Admin­istration under the Controlled Substances Act, indicating they can be abused or lead to drug dependence.

It has been suggested perampanel is liable to be abused at high doses; it pro­duced euphoria similar to ketamine. The psychogenic effects of these compounds with abuse potential are the result of their systemic effects within the CNS. In using the Direct Effects non-systemic topical neuro-affective drug delivery, such unde­sirable effects are avoided.

As with other anticonvulsants, FY­COMPA may make one dizzy, sleepy, or tired; other possible effects include aggres­sion, hostility, irritability, anger, and homi­cidal ideation and threats, particularly in the setting of prior history of aggressive behavior or with concomitant use with other drugs which can have such effects.

DIRECT EFFECTS™

Direct Effects is a patented topical drug delivery system that capitalizes on the fact that the CNS and skin are both de­rived from the embryologic tissue, neu­roectoderm. As such, they communicate with each other directly and continuously. Cutaneous free nerve-endings under the skin surface, the stratum corneum, have receptors to neurotransmitters functioning in CNS. Accordingly, specially formulated neuro-active drugs as topical cream can be applied to the skin at the Back of the Neck at the Hairline, BONATH™, to acti­vate these receptors to cause nerve action potentials to brain to produce specific ther­apeutic effects. In some 30 different neuro-active compounds studied to date using this technology, therapeutic benefits were found within 3-5 minutes with all compounds, reflecting the fact that nerve conduction from skin to CNS is essentially the same for all individuals. However, such is not the case with systemic drug delivery in which variables in GI absorption, he­patic metabolism, and cardiovascular and hemodynamic factors are involved. There are also restrictions by the blood-brain barrier (BBB). See Figures 1 and 2.

We have also observed that if a “dys­functional state” within CNS with associ­ated symptoms does not exist, a topically applied drug at BONATH has no effect, al­luding to the fact that skin-brain neural communication is constant, reflecting the connectivity between the two and provid­ing each other information on their re­spective electrochemical states at any one time.

Accordingly, Direct Effects drug deliv­ery is an ideal means to study an anti-epileptic drugs, such as perampanel (FYCOMPA) to determine its effects on symptoms experienced by patients with epilepsy. As a glutamate AMPA receptor antagonist, perampanel acts to control seizures through suppressing neuronal hy­peractivity. As discussed, in addition to seizures, there are many other manifesta­tions of neuronal hyperactivity present in patients with epilepsy. These conditions may also be benefited. If there is therapeu­tic benefit through Direct Effects topical perampanel cream application at BON­ATH, EEG changes from baseline should be observed after treatment.

PATIENT DEMOGRAPHICS

106 patients with seizures, various en­cephalopathies on anticonvulsants, and other neurological conditions with abnor­mal EEGs were studied; 61 female and 45 male, ages 12-84 years. Response to treatment was measured with a 0-10 pain scale, Hamilton Depression Scale, HAM-D, and EEG (Table 1).

RESULTS

Relief of head pain within 5 minutes of topical drug application was reported in all 15 patients presenting with headache as their most prominent symptom. A num­ber experienced complete resolution of their moderate-to-severe headache. There was also improvement in other symptoms, as noted further:

• Decreased anxiety and agitation, less impulsive: 20 patients
• Cognitively improved with better speech and expression, more engaged: ⁶ pa­tients
• Decrease in dizziness, nausea, less tremulous: 12 patients
• Increased focus and alertness: 8 pa­tients
• Decreased neck stiffness and pain: 4 patients
• The most prevalent and striking change noted in treated patients was that of im­proved “clarity and brightness of eyes,” in over 90% of patients

In six patients, EEGs were recorded concurrently with application of topical perampanel 2mg/ml. In all six subjects, EEGs improved within 3-5 minutes of drug as either resolution or attenuation of an epileptic focus; and/or, stabilization of background with better delineation of an underlying seizure focus.

TOPICAL PERAMPANEL AS ABORTIVE AGENT

There were two examples of patients actively seizing, in “status epilepticus,” whose seizures stopped within minutes of 2 mg/ml topical perampabel application:

Joanne E: 84 y/o female with left hemi­sphere stroke and continuous right facial focal motor seizures. EEG revealed left temporal spike focus. After treatment, right facial focal motor seizures resolved and the patient became more alert and re­sponsive with improved speech. Patient had been on Carbamazepine, Trileptal, and Valium without benefit (Figure 3).

Rita B: 52 y/o female with seizures brought in unresponsive after her usual episodes of eyes twitching followed by un­steadiness and loss of consciousness, oc­curring several times per week. Following treatment, the patient awoke within min­utes and became responsive, following commands, and was able to walk out of the office unassisted.

OTHER EEG CHANGES AFTER TOPICAL PERAMPANEL

Various changes in baseline EEG oc­curred in patients with epilepsy, depending on the overall hyperexcitable state of the brain at the time. If it was in an abnormal excitable state with seizure foci noted and disorganized background, within minutes of application of topical per­ampanel, the seizure focus resolved, and the background normalized (Figure 4).

If, on the other hand, the baseline EEG was significantly disorganized with no obvious seizures, treatment stabilized the background with emergence of an existing epileptiform focus (Figure 5).

CONCLUSIONS

Direct Effects topical perampanel (FYCOMPA), Fyco-Top, is effective in treating headache and other neurological symptoms commonly encountered in pa­tients with seizures and other conditions in which neuronal instability and hyper-ex­citability exist. As AMPA glutamate receptor antagonist acting to reduce neuronal ex­citability, it is not surprising that peram­panel acts beneficially in this manner. Additionally, in using Direct Effects with topical neuro-affective drug activity on re­ceptors of cutaneous free nerve-endings with direct neural connections to CNS, therapeutic benefits are rapidly observed without systemic side effects or drug inter­actions.

Sasha Feygin and Daniele La Rosa are premedical student volunteers who as­sisted in the collection, tabulation, and in­terpretation of data.  

 REFERENCES

1. Spichak, S., Signs and Symptoms of Epilepsy, Health,April 21, 2024.
2. FYCOMPA® Package Insert, Catalyst Pharmaceuti­cals, Coral Gables, FL 33134, 2023.
3. Hoffmann, J. and Charles, A., Glutamate and Its Receptors as Therapeutic Targets for Migraine, Neurotherapeutics. 2018 Apr; 15(2): 361–370.
4. Aung-Din, R. and Martin, C., NeuroDirect™ Keta­mine: Novel, Non-Systemic Topical Therapy for PTSD & Associated Intractable Depression, Devel­opment & Delivery March 2023 Vol 23 No 2, 32-37.
5. Aung-Din, R. and Martin, C., Topical NeuroDirect™ Ketamine in the Treatment of Neuropathic Pain Syn­dromes: Fibromyalgia, Neuropathy, Radiculopathy & Causalgia/Complex Regional Pain Syndrome, Drug Development & Delivery Octoberr 2023, Vol 23 No 7, 59-65.
6. Rogers, L., What to Know About Ketamine:The anesthetic is being used off-label for everything from psychiatric illnesses to autoimmune diseases, JOHNS HOPKINS BLOOMBERG SCHOOL of PUB­LIC HEALTH, January 26, 2024.
7. Paul, I. and Skolnick, P., Overview of Major Depres­sive Disorders, Ann. N.Y. Acad. Sci. 1003:250-272, 2003.
8. Mitchell, N. and Baker, G., An Update on Role of Glutamate in the Pathophysiology of Depression, ActaPsychiatrica Scandinavica, Vol.122:3, 192-210, July 2010.
9. Spravato esketamine HCL Package Insert, Jannssen Pharmaceuticals, 2019.

Dr. Ronald Aung-Din practices General Neurology & Neuro-Psychiatry in Sarasota, FL. He attended the University of Texas Southwestern Medical School, Dallas, TX, followed by residencies in Neurology and Neurosurgery at University of Florida. He has participated in over 60 pharmaceutical industry-sponsored clinical trials, functioning as Principal Investigator in drug research studies. He is also active in treating varied neurological and psychiatric conditions using delivery of CNS-active drugs with Direct Effects™ technology, for which 13 US and foreign patents have been granted to date with others pending. AfGin Pharma, LLC was founded in 2009 to advance the unique nature of this non-systemic drug delivery and its goal of Enhanced Neuro-Therapeutics through Direct Effects Topical Technology.