The effect of a synthetic steroidal anti‐androgen, TZP‐4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5–9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP‐4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day P.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP‐4238 (Group 2) or CMA (Group 3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP‐4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP 4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP 4238 treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP‐4238 is a potent anti‐androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells. Acta Pathol Jpn 42: 151–157, 1992.

Abstract-Theinhibiting influences of some non-steroidal anti-inflammatory drugs (NSAIDs) and other agents on cyclooxygenase (CO) and lipoxygenase (LO) activities in some enzyme preparations were investigated. Washed rat platelets (CO and 12-LO), rat polymorphonuclear leukocytes (PMNs, CO and 5-LO), rat renal medulla homogenate (CO), and purified soybean LO (15-LO) were used as enzyme preparations.The IC50 values of drugs on the enzyme activities were determined in each preparation.In addition, the inhibitory activities of the drugs on the generation of chemiluminescence from PMNs stimulated by phorbol myristate acetate were tested.NSAIDs (indomethacin, ketoprofen and phenylbutazone) showed a selective inhibition of CO in each preparation, but benoxaprofen inhibited both enzymes, especially in PMNs. BW755C, 1 -phenyl-3-pyrazolidone (phe nidone), toluene-3,4-dithiol (dithiol), 6-ethoxy-1,2-dihydro-2,2,4-trimethyl quinoline (ethoxyquin) and acetone phenylhydrazone (APH) inhibited both enzyme activities.Nordihydroguaiaretic acid (NDGA) showed a relatively selective in hibition of LO in all the preparations used. APH inhibited soybean 15-LO markedly compared with the other enzymes tested.Ethoxyquin inhibited COs more markedly than LOs, and with regard to LO inhibition, it inhibited 5-LO in PMNs markedly. BW755C, phenidone, ethoxyquin, NDGA, APH and dithiol, which strongly inhibited 5-LO, showed an inhibitory activity on the generation of chemiluminescence from PMNs activated with phorbol ester.

The effect of a synthetic steroidal anti-androgen, TZP-4238, O M steroid-induced canine prostatic hyperplasia was studied by light and electron microscopy. Male beagle dogs (1-2 years old) were divided into four experimental groups. Group 1 consisted of intact controls. The other animals were castrated. The castrated animals were treated for 25 weeks with 1) 5~-androstane-%a, 17g-diol (Adiol) plus 17g-estradiol (E,)(Group 2), 2) A-diol plus E,+ TZP-4238 0.5 mg/kg (Group 3) and 3) A-diol plus E,+ chlormadinone acetate (CMA) 2.5 mg/kg (Group 4). TZP-4238 and CMA were administered orally for 2 1 weeks after 4 weeks treatment with A-diol plus E, .In group 2, glandular hyperplasia of the prostate was clearly noted. In contrast, combined treatment with TZP-4238 (Group 3) or CMA (Group4) produced marked atrophy of the glandular epithelium. Loss of secretory and metabolic activities was confirmed by ultrastructural investigations. Our data indicate that TZP-4238 is a potent anti-androgen for the prevention of canine prostatic hyperplasia i n the steroidinduced benign prostatic hyperplasia (BPH) model. Acta Pathol Jlpn 40: 871-879, 1990.

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