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Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

Administration, Intravesical↗

Effect of prostaglandin F2 alpha treatment before norgestomet and estradiol valerate treatment on regression, formation, and function of corpora lutea in beef heifers.

Two experiments were conducted to determine if corpus luteum regression, formation, and function were associated with the decreased calving rate observed in beef females administered PGF2 alpha 5 days before Syncro-Mate B (SMB) treatment. Experiment 1 included 31 beef heifers 11 to 13 months old and experiment 2 included 31 beef heifers 19 to 21 months old. Heifers were randomly assigned to 1 of 2 groups (control and PGF2 alpha 5 days before SMB treatment). Heifers were bled 10 days before PGF2 alpha treatment, immediately before PGF2 alpha and SMB treatments, at the time of implant removal, and twice weekly after implant removal. Heifers in experiment 2 were observed twice daily for estrus for 5 days after PGF2 alpha treatment and for 3 days after norgestomet implant removal. Based on the blood samples collected before SMB treatment, 15 heifers in experiment 1 and every heifer in experiment 2 were with estrous cycles. All heifers in experiment 1 had progesterone concentrations < 0.5 ng/ml 2 days after implant removal. However, progesterone concentrations during the luteal phase in control heifers with estrous cycles were higher (P < 0.05) than in PGF2 alpha treated heifers with estrous cycles and in heifers previously without estrous cycles. In experiment 2, based on the occurrence of estrus and progesterone concentrations, heifers were also classified as metestrus or diestrus at the time of SMB treatment. The data were analyzed as a 2 x 2 factorial with treatment (control or PGF2 alpha) and stage of the cycle (metestrus and diestrus) as main effects. More metestrus heifers (40%) had progesterone concentrations > 1.0 ng/ml 2 days after implant removal than diestrus heifers (0%). In addition, progesterone concentrations during the luteal phase in metestrus heifers were lower (P < 0.05) than in diestrus heifers. PGF2 alpha treatment had no effect (P > 0.25) on the number of heifers with > 1.0 ng/ml progesterone 2 days after implant removal and progesterone concentrations during the luteal phase. There was no treatment by stage of the estrous cycle interactions. In summary, the administration of PGF2 alpha 5 days before SMB decreased the calving rate by causing more heifers to be metestrus at SMB treatment. Fewer metestrus heifers (than diestrus heifers) were synchronized (with < 1.0 ng/ml of progesterone 2 days after implant removal) to SMB treatment and those synchronized had lower progesterone concentrations during the luteal phase.

Animals↗

Norgestomet- and oestradiol valerate-induced luteolysis is dependent upon the uterus.

Beef heifers were assigned to three groups: (1) untreated controls (n=4), (2) Syncro-Mate B(R) (SMB)-treated (n=5), and (3) hysterectomized and SMB-treated (n=4). SMB was administered 8 or 9 days after oestrus, approximately 30 days after hysterectomy. This study was conducted to determine if the uterus was necessary for SMB to induce luteolysis. SMB induced premature luteolysis as only 20% of the intact SMB-treated heifers had >/=0.75 ng/ml of progesterone 7 days after the time of SMB treatment, compared to all (100%) of the untreated heifers (p<0.05). By 9 days after the time of SMB treatment, 25% of the untreated heifers and none (0%) of the intact SMB-treated heifers had >/=0.75 ng/ml of progesterone; however, all (100%) of the hysterectomized SMB-treated heifers had >/=0.75 ng/ml of progesterone (p<0.05). Therefore, SMB-induced luteolysis required the involvement of the uterus. The luteolysin, prostaglandin F(2alpha), is probably the secretion from the uterus that mediates the SMB-induced luteolysis. SMB treatment, however, required 7-8 days to induce luteolysis.

Animals↗