Valnoctamide as a Valproate Substitute With Low Teratogenic Potential: Double-Blind Controlled Clinical Trial

Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its well-known teratogenicity limits its use in young women of childbearing age (1-3). The alternative mood stabilizers such as lithium and carbamazepine also have teratogenic potential so the treatment of bipolar disorder in young women is problematic. The difficulties are particularly acute in those young women patients who respond well to anti-bipolar therapy and maintain or begin normal interpersonal and marital relations and desire to have children.

One approach to this problem has been the search for valproic acid derivatives with less teratogenic potential (4). According to toxicologic studies the teratogenicity of valproate stems from its free carboxylic group (2, 3). Valpromide is an amide derivative of valproate without the suspect free carboxylic group. It was synthesized and marketed and has anticonvulsant efficacy, at least as good as valproic acid (1). There are some reports of its efficacy in bipolar disorder as well (5). In some animal species, only a small amount of valpromide is metabolized to valproic acid. However, in humans valpromide is metabolized to a large degree to valproic acid and so it does not solve the problem of teratogenicity (1, 6).

Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does not undergo biotransformation to the corresponding free acid (6-9). In animal studies it is at least as anticonvulsant as valproate and valpromide (1, 6, 10). It has been marketed as an anxiolytic and sedative in several European countries (as Nirvanil) including Italy, Holland and Switzerland but has not actively been promoted as an anticonvulsant. It was marketed in the USA as Axiquel by McNeil in the 1970's. Unfortunately, despite considerable efforts we have not been able to obtain pharmacovigilance data from this period. Given its equivalence to valproate and valpromide as an anticonvulsant in animal models of epilepsy (1, 6, 10), it is reasonable to assume that valnoctamide is also anticonvulsant in humans. It is also likely or at least possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown to be distinctly less teratogenic than valproate (11). Injection at day 8 of gestation produced only 1percent exencephaly (as compared to 0-1percent in control mice and 53 percent in valproate treated mice). Embryolethality rates showed similar results: 52 percent with valproate vs. 5percent in the controls and 2 percent with valnoctamide.

Valnoctamide's patent is expired (12) and it is not the property of any major pharmaceutical company. Pharmaceutical company support cannot be obtained for our trial; therefore it is investigator initiated.

Valnoctamide will be synthesized for our study by Banyan Chemical in India (which has been inspected by the FDA) by GLP (good laboratory practice) in a manner acceptable for human use by the Israel Ministry of Health (and in principle for an IND by the FDA). Banyan manufactures at the same site generic compounds, atenolol for instance, sold in the USA and distributed by international companies, Novartis for instance.