Comparative teratogenicity analysis of valnoctamide, risperidone, and olanzapine in mice.
OBJECTIVE
Based on the recent findings from animal studies, it has been proposed that the therapeutic use of valnoctamide, an anxiolytic drug developed in the early 1960s, be extended to treat other neurological disorders such as epilepsy and bipolar disease. Given the scarcity of adequate data on its prenatal toxicity, a comparative teratogenicity study of valnoctamide and two of the most commonly used drugs to treat bipolar disorder, risperidone and olanzapine, was carried out in a mouse model system.


METHODS
Pregnant dams were treated with the aforementioned three drugs at the dose levels calculated as an equal proportion of the respective LD50 values of these drugs. The main reproductive indices examined included the numbers of implantations and resorptions, viable and dead fetuses, and fetal gross, visceral and skeletal abnormalities.


RESULTS
The outcomes of the present study indicated that olanzapine was the most teratogenic of the three drugs, inducing maternal-, embryo-, and fetotoxicity. Risperidone also exerted a significant prenatal toxicity, but its adverse effect was less pronounced than that induced by olanzapine. Valnoctamide did not show any teratogenic effect, even when used in relatively higher dosages than olanzapine and risperidone. The observed increased skeletal abnormalities in one of the valnoctamide treatment groups were nonspecific and, as such, signaled a modest developmental delay rather than an indication that the compound could induce structural malformations.


CONCLUSIONS
Under our experimental conditions, valnoctamide demonstrated the lowest prenatal toxicity of the three tested drugs.
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
Bogdan J
BJ
Wlodarczyk
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
Krystal
K
Ogle
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
Linda Ying
LY
Lin
School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Meir
M
Bialer
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.|Department of Chemistry and Biochemistry, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
Richard H
RH
Finnell
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects; D001714:Bipolar Disorder / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D000077152:Olanzapine; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects; D064793:Teratogenesis / Q000187:drug effects*
D000577:Amides; D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; C045179:valnoctamide; D018967:Risperidone; D000077152:Olanzapine
comparative teratogenicity; mice; olanzapine; risperidone; valnoctamide