Valrocemide|92262-58-3|安捷凯

Background

Epilepsy is a chronic condition requiring long-term drug treatment, often for the patient's entire life. Valrocemide is an anticonvulsant agent under development by Teva and Acorda as a therapeutic for the treatment of epilepsy.

In vitro: It was found that 1 mM of valrocemide could drastically inhibit human brain crude homogenate MIP synthase activity. Furthermore, the mechanism of the effect of valrocemide were studied and results showed that valrocemide reduced the enzyme activity by an apparent competitive mode of inhibition [1].

In vivo: In mice, valrocemide showed complete protection against maximal electroshock-, pentylenetetrazole-, picrotoxin-, bicuculline-induced seizures as well as 6-Hz "psychomotor" seizures with ED50 values of 151, 132, 275, 248, and 237 mg/kg, respectively. Valrocemide was also effective in preventing sound-induced seizures in Frings audiogenic-seizure susceptible mice. The neurotoxic dose in mice was 332 mg/kg. After oral administration to rats, valrocemide was active in the maximal electroshock test, with an ED50 of 73 mg/kg, and the median neurotoxic dose was 1,000 mg/kg. IP administration of 300 mg/kg of valrocemide to hippocampal kindled SD rats blocked generalized seizures and shortened the afterdischarge duration significantly. Valrocemide also had complete protection from focal seizures in the corneally kindled rats [2].

Clinical trial: Valrocemide is a new antiepileptic drug currently undergoing phase II clinical trials in patients with refractory epilepsy [2].

参考文献:
[1] Shaltiel G,Mark S,Kofman O,Belmaker RH,Agam G.? Effect of valproate derivatives on human brain myo-inositol-1-phosphate (MIP) synthase activity and amphetamine-induced rearing. Pharmacol Rep.2007 Jul-Aug;59(4):402-7.
[2] Isoherranen N,Woodhead JH,White HS,Bialer M.? Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug. Epilepsia.2001 Jul;42(7):831-6.

Protocol

Animal experiment:

Rats: Effect of valrocemide on the afterdischarge threshold in hippocampal kindled rats is evaluated in rats kindled according to this procedure. On the day of the test, the individual rat's afterdischarge threshold is determined by increasing the current intensity stepwise until the rat displayed an electrographic afterdischarge with duration of 4 s. For afterdischarge threshold determination, the initial stimulation is conducted at 20 μA and increased in 10-μA increments every 1–2 min until an afterdischarge is elicited. After administration of valrocemide, the individual rat's afterdischarge threshold is redetermined at times 0.5, 1, 2, and 4 h; ADD and BSS are recorded at each time point and compared with the control values obtained before drug administration. The criteria for seizure scoring is as described earlier for corneally kindled animals[1]. Mice: The intravenous (i.v.) pentylenetetrazole seizure threshold test (i.v. Met) also is used. At the TPE of valrocemide, infusion (0.34 ml/min) of 0.15% heparinized solution of pentylenetetrazole (0.5%) is started into the tail vein of a mouse, and the times to the appearance of the first myoclonic jerk and the subsequent sustained clonic seizure are recorded. A group of 10 drug-treated (132 mg/kg valrocemide, i.p.) mice is compared with 10 vehicle-treated controls. The time is converted to the dose of pentylenetetrazole in mg/kg. The i.v. Met test is performed according to the same procedure also after prolonged administration of valrocemide daily, i.p. (132 mg/kg) for 5 consecutive days[1].

参考文献:

[1]. Isoherranen N, et al. Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug. Epilepsia. 2001 Jul;42(7):831-6.