A short term study and clinical application to evaluate the safety and effect of vasopressin 2 receptor antagonist (Tolvaptan, OPC-41061) in dogs

Abstract

In veterinary medicine, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a rare disorder and only two successful treatment options have been reported. In human medicine, on the other hand, SIADH is relatively well defined and various treatment options have been reported. In recent times, the vasopressin 2 receptor antagonist has been developed and is widely used to treat SIADH. The aims of this study were to evaluate the safety and efficacy of tolvaptan, the vasopressin 2 receptor antagonist, and to establish the therapeutic dosage for dogs. Tolvaptan was given to groups of normal beagle dogs, including control, 0.5 ㎎/㎏ SID, 3 ㎎/㎏ SID, and 5 ㎎/㎏ SID at preset doses for three days. Complete blood cell count, serum biochemistry profile, serum osmolarity calculation, and urine specific gravity measurement were performed at the time of each 0, 4, 8, 12, 24, 48, and 72. Without decreased levels of urine specific gravity in the groups of 3 ㎎/㎏ and 5 ㎎/㎏ within 4 hours after drug administration, there were no abnormalities or significant changes. While there were no significant changes in the groups of normal beagle dogs, remarkable improvements of serum sodium concentration and serum osmolarity were observed in the SIADH dog, who had received orally administered tolvaptan at doses of 3 ㎎/㎏ SID. Serum sodium increased gradually from 134 to 141 mmol/L within 35 hours. Calculated serum osmolality also increased from 281.56 to 292.25. Compared with the groups of control and 3 ㎎/㎏ SID, changes of serum sodium concentration and serum osmolarity in the SIADH dog, who had received orally administered tolvaptan at doses of 3 ㎎/㎏ SID, revealed statistical significance (p<0.0001). The dog has continued to receive tolvaptan at 3 ㎎/㎏ SID in the 9 months since the trial, and there have been no further clinical signs of hyponatremia: the dog shows normonatremia and plasma normoosmolarity without any abnormalities. Although tolvaptan carries the potential risks of liver injury and central pontine myelinolysis with careless use, the results of this study suggest that the administration of tolvaptan to treat SIADH is an effective alternative if fluid restriction does not sufficiently correct electrolyte imbalance.