What Is Ezogabine?

Potiga is approved for the treatment of common local epilepsy seen in patients with epilepsy, and is the first neuronal potassium channel opener developed for the treatment of epilepsy. However, the mechanism of action has not been clearly defined. The drug can be used as an antispasmodic drug to reduce excitability by stabilizing neuronal potassium channels in an "open" state.

Potiga

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Potiga is approved for the treatment of common local epilepsy seen in patients with epilepsy, and is the first neuronal potassium channel opener developed for the treatment of epilepsy. However, the mechanism of action has not been clearly defined. The drug can be used as an antispasmodic drug to reduce excitability by stabilizing neuronal potassium channels in an "open" state.

Commercial name	Potiga	common name	ezogabine
Chinese name	Izagabin	approve the time	year 2011
Route of administration	oral	Active ingredient	EZOGABINE
Molecular formula	C16H18FN3O2	Molecular weight	303.331g / mol
Approval Number	NDC0173-0812-59	Medication instructions	HaoeyouHealthcare

On June 13, 2011, the US FDA approved ezogabine tablets for the adjuvant treatment of partial seizures in adults. This drug is the first neuronal potassium channel opener for epilepsy.

ezogabine

POTIGA is a calcium channel opener suitable for the treatment of partial seizures in patients 18 years and older

Tablets, 50mg, 200mg, 300mg and 400mg

1. Dosing 3 times a day with or without food.
2. The initial dose should be 100 mg 3 times a day (300 mg / day) for 1 week.
3. Adjust to the maintenance dose by increasing the dose at intervals of not more than 150 mg / day.
4. Optimize the effective dose between 200mg 3 times a day (600mg / day) to 400mg 3 times a day (1,200mg / day).
5. In a controlled clinical trial, 400 mg 3 times a day (1,200 mg / day) compared to 300 mg 3 times a day (900 mg / day) showed limited improvement, increased adverse effects, and discontinuation of the drug.
6. When stopping POTIGA, gradually reduce the dose over a period of at least 3 weeks.
7. Adjust dose for elderly patients and patients with moderate to severe renal or liver impairment.

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The most common adverse reactions (incidence 4% and nearly twice the placebo) were dizziness, drowsiness, fatigue, confusion, dizziness, tremor, abnormal coordination, diplopia, attention deficit, memory impairment, weakness, blurred vision, gait Instability, aphasia, dysarthria, and balance disorders.

1. Ezogabine plasma levels may be reduced by concomitant administration of phenytoin or carbamazepine. Consideration should be given to increasing the POTIGA dose when adding phenytoin or carbamazepine.
2. N-acetyl metabolite of Ezogabine may inhibit renal clearance of digoxin, a P-glycoprotein substrate. Monitor digoxin levels.

Pregnancy: May cause fetal harm based on animal data. Pregnancy registration is available.
Pediatric use: Safety and effectiveness have not been established in patients under the age of 18.

1. Urinary retention: Patients should be carefully monitored for urinary symptoms.
2. Neuropsychiatric symptoms: Monitor confusion, psychotic symptoms, and hallucinations.
3. Vertigo and drowsiness: Monitor dizziness and drowsiness.
4. QT prolongation: QT interval should be monitored in patients who are taking medications known to increase QT interval or who have certain cardiac conditions.
5. Suicidal behaviors and ideas: Monitor suicidal thoughts and behaviors.

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In the traditional MES (Maximum Electrical Shock Convulsion) test, mice and rats were injected intraperitoneally with retigabine and stimulated with a large current. This product showed effective anticonvulsant effects, with ED50 of 9.3 and 5.1 mg.kg-1, respectively. And oral administration of this product can also produce the same effect, indicating that this product has good system bioavailability. A series of mouse tests have shown that this product can also effectively antagonize chemically induced seizures, such as dose-dependently inhibiting clonic convulsions caused by subcutaneous injection of pentylenetetrazol and Azadirachtavirus, with ED50 of 13.5 and 18.6 mg, respectively. .kg-1; Relieves ankylosing forelimb extension or clonic epilepsy caused by injection of N2 methyl 2D-aspartic acid (NMDA, 3g / 5L or 012g / 5L) in the lateral ventricle; Seizures induced by base and strining 30mg.kg-1 have antagonistic effects.
A commonly used human model of prevention of partial seizures--a rat model of focal epilepsy with amygdala ignited by focal electrical epilepsy shows that this product can produce a dose-dependent anticonvulsant effect after oral and intraperitoneal injection. At low doses [0.01 (ip) and 0.1 (po) mg.kg-1] can significantly increase the post-discharge threshold, and at high doses [2.5 to 5 (ip) and 10 to 15 (po) mg.kg-1 ] Will also affect other seizure parameters in model rats, such as the severity and duration of seizures and the duration of post-discharge; at the dose of 015 mg.kg-1 (ip), it can significantly inhibit the amygdala-type seizures, But 0.1 and 1 mg.kg-1 (ip) doses are not effective.
Initial research on the anticonvulsant mechanism of this product showed that this product can block sodium and calcium currents and enhance GABA-induced currents in neuronal cells. Other studies have shown that this product can more effectively reverse the effects of 4-aminopyridine-induced hyperexcitation and epileptiform discharge in hippocampal brain slices than other control compounds, and increase the amount of newly synthesized GABA in hippocampal brain slices. The latest research shows that this product is a neuronal potassium channel opener and GABA enhancer, which can reduce neuronal excitability. This shows that the anticonvulsant effect of this product has multiple mechanisms. Most antiepileptic drugs act on sodium and calcium channels or different GABA receptors.

Pharmacokinetic tests in rats and dogs have shown that due to the lack of extensive first-pass effects, a single dose of retigabine can achieve higher blood concentrations and lower plasma drug clearance, and In dogs, the terminal half-life is longer; the individual pharmacokinetic differences between rats are small; in dogs, the plasma protein binding rate of this product is low enough to avoid interaction with drugs with high protein binding rates.
In rats and dogs experiments, this product has not been observed to have any acute and subchronic toxicity, and no genotoxic effect. Clinical study In a large-scale phase II clinical trial, patients were divided into 4 groups, receiving retigabine 600, 900, and 1200 mg.d-1 and placebo, respectively. As a result, the median seizure rates in the four groups of patients decreased by 23%, 29%, 35%, and 13%, respectively, showing that the efficacy of the two high-dose groups was significantly higher than that of the placebo group. A randomized clinical trial in 73 patients with partial epilepsy compared the safety of the three dosing regimens of this product: all subjects initially received this product at a dose of 300 mg.d-1, followed by treatment The dose was gradually increased to the target dose of 1200 mg.d-1, in which the fast increasing group, the medium increasing group and the slow increasing group reached the target dose after 13, 25 and 42 days, respectively. As a result, the number of subjects withdrawing from treatment due to adverse reactions in each group was 43.5%, 31.8%, and 13.0%, respectively.
In another double-blind, randomized clinical trial, 399 patients with refractory partial-onset epilepsy were treated with placebo and this product (200, 300, or 400 mg, tid), respectively, and they were co-administered with other antiepileptic drugs. 220 subjects completed the trial and participated in the next extended open-label trial. In the open-label test, subjects received concurrent treatment with this product (300 mg, tid; subsequent dose reduction or increase to a maximum dose of 1200 mg.d-1) and other antiepileptic drugs. By the end of the open-label trial, compared with before treatment, the median monthly reduction rate of the total partial seizure frequency of the subjects was 48.3%; at 3 and 6 months, those who withdrew from the trial mainly due to adverse reactions of the central nervous system The subjects were 8% and 18%, respectively.
GlaxoSmithKline / Valeant Pharmaceuticals has recently submitted a market application for retigabine to assist in the treatment of partial epilepsy in Europe and the United States, which is based on two key phase III clinical trials. One of the trials, called RESTORE1, involved 306 patients with refractory partial-onset epilepsy. Subjects were treated with this product (1200 mg, tid) or placebo while using one other antiepileptic drug; and the other In the RESTORE2 trial, more than 1,000 patients received normal antiepileptic drugs while taking 600, 900 mg or placebo of this product, respectively. As a result, both trials met their common primary endpoint evaluation index expectations, that is, a 28% to 40% reduction in the total portion and frequency of patients in this product for 28 days (16% in the placebo group) and a curative effect response rate ( The proportion of subjects whose onset frequency was reduced by more than 50% on 28 days was 39% to 47% (19% in the placebo group); common adverse reactions included dizziness, fatigue, palpitations, dizziness, tremors, abnormal coordination, and diplopia , Attention disorders, weakness, and blurred vision.
In addition, a phase II clinical trial of this product for the treatment of postherpetic neuralgia is also ongoing.

Potiga was established in 3 multicenter, randomized, double-blind, placebo-controlled studies of the efficacy of adjuvant therapy in 1239 adult patients with localized episodes. The primary end point included the percentage change in baseline attack frequency during the double-blind treatment phase.
Participants in the study had partial epilepsy W / W / O secondary summaries and 1 to 3 concomitant antiepileptic drugs. W / W / O concomitant stimulation of the vagus nerve was not adequately controlled. More than 75% of patients take 2 or more concomitant antiepileptic drugs. At the 8-week baseline period, patients had no seizures for more than 3 to 4 weeks, with an average of at least 4 partial seizures every 28 days. The average duration of epilepsy is 22 years. Across 3 studies, the median baseline seizure frequency was seized from 8th to 12th of each month. The standard of statistical significance was P <0.05;
Patients were randomized to 600 mg / day, 900 mg / day, or 1200 mg / day, every 3 doses equal to the total daily maintenance dose. During the titration of all three study phases, the treatment started at a 300 mg / day growth target maintenance dose and the 150 mg dose was increased weekly. A 600mg / day dose (Study 1) with Potiga observed a statistically significant effect, at 900mg / day (Studies 1 and 3) and a median reduction of 28% at 1200mg / day (Studies 2 and 3)-one day Frequency of attacks (baseline double-blind phase) compared to placebo in all 3 studies.