110 



Fig. 1. Structural formulas of orotic acid and 5-fluoroorotic acid. 



worked out completely, sufficient data have been collected to warrant the 

 conclusion that the neurologic eflfects of these compounds are attributable, 

 directly or indirectly, to disturbances in pyrimidine nucleotide or nucleic 

 acid metabolism or both. 



Intracisternal Administration 



Intracisternal administration of 5-15 mg of sodium salt of FO (or 2-5 mg 

 FUR) in cats produces a progressive rhombencephalopathy and, in some 

 animals, a cervical myelopathy ( Koenig, 1958c). Signs of nemal dysfunction 

 appear on the 4th to 6th day after injection. The first indication of disease is 

 a mild clumsiness of gait, which worsens in time. The gait becomes broad- 

 based, unsteady and dysmetric. Decomposition of movement, oscillation of 

 trunk and limbs, and reeling gait complete the picture of cerebellar ataxia. 

 This usually becomes so disabling that the animal is incapable of locomotion 

 or alimentation by the 2nd or 3rd week after injection of the antimetabolites. 

 Many animals have signs of neuronal irritation, including fasciculations of 

 facial musculature, myoclonic jerks of lorelimbs, and various tonic and 

 runnings seizures. Animals die of inanition, seizures, or bulbar failure by the 

 3rd week. Outstanding pathologic distmbance is a depletion of Nissl sub- 

 stance in Purkinjc neurons of the cerebellum and in neurons of the brain 

 stem and cervical spinal cord. 



Intraspinal Injection 



Injection of FO into the lumbar subarachnoid space ( 10-15 mg divided 

 into two doses and injected 3-4 hours apart ) in cats produces a progressive 

 myelopathy, which becomes evident on the 2nd or 3rd day (Koenig, 1960). 

 FUR and FCR produce a similar disorder in doses of 2-4 mg. Signs of 

 neuronal irritation appear first. These consist of muscle fasciculations, hyper- 

 esthesia, and sometimes myoclonic jerks in the hindquarters (Fig. 2) and 

 are associated with clumsiness, mild weakness, enhanced stretch reflexes, and 



