GENERAL PHARMACOLOGY OF TA-058, A NEW SEMISYNTHETIC PENICILLIN

Abstract

General pharmacological activities of TA-058 were studied.
TA-058 did not show any of the following activities pertaining to the central nervous system in mice or rats at an intravenous dose of 1, 000 mg/kg: muscle-relaxant, hypnotic-potentiating, anticonvulsive, sedative, anti-apomorphine, anti-methamphetamine, anti-physostigmine, anti-depressive, analgesic, hypothermic and antipyretic activities. No drug-related changes were observed on the spontaneous EEG in rabbits and in the spinal reflex potentials in cats (300 mg/kg, i.v.).
For the cardiovascular system, TA-058 only slightly increased the mean arterial blood pressure and heart rate in anesthetised rats, but only less than 20 % at 1, 000 mg/kg, i.v. In anesthetised dogs, no changes were observed in the mean arterial blood pressure, heart rate and renal blood flow at 300mg/kg, i. v. The respiratory rate and femoral (at 100mg/kg, i. v.) and commoncarotid blood flow (at 300mg/kg, i.v.) increased rapidly but transiently. Since similar changes in the cardiovascular parameters were produced by intravenous injection of an iso-osmotic solution of mannitol (ca. 1, 500 mOsm), it may be concluded that these changes were mainly due to the hyperosmolarity of the TA-058 solution.
In conscious rats, Na- and Cl-excretion in 5 hr.-urine were decreased slightly but significantly after single subcutaneous administration of 1, 000mg/kg or daily administration of 300 mg/kg/day for 8 consecutive days. In the latter experiment, a slight decrease in urinary volume was also observed. The growth curve was not affected by the daily administration. Since any signs of severe renal toxicity have not been reported in the subacute and chronic toxicity tests of TA-058, this antibiotic probably causes no serious side effects on the renal function.
TA-058 exerted no effects on the gastrointestinal system at 1, 000mg/kg (i.v. or s.c.) except for a slight decrease in gastric juice volume and free HCl concentration in rats.
TA-058 neither contracted nor relaxed isolated smooth muscle preparations such as guinea pig ileum and was deferens and rat uterus even at a concentration as high as 10^-3g/ml: anti-Ach, anti-histamine (H₁ and H₂), ganglion blocking, adrenergic alpha-blocking, anti-oxytocin and papaverine-like activities were not observed
TA-058 did not have any anti-inflammatory and local anesthetic activities.
These results indicate that TA-058 is a pharmacologically inert substance.