Butorphanol.

Butorphanol (Stadol) is a synthetic agonist-antagonist analgesic from the 14-hydroxymorphinan series. Animal studies display analgesia, antitussive effects, low gastrointestinal activity, limited respiratory depression, some cardiovascular and skeletal muscle actions, diuresis, slight miosis and opiate antagonism. Butorphanol is metabolized in the liver with renal excretion, yielding a half-life of 3-4 h. Pain relief is good to excellent with parenteral administration in 90% of patients with moderate to severe pain. Surgical anesthetic indications involve preoperative and preinduction supplementation, balanced anesthesia and postoperative pain. Side effects are sedation, nausea, elevated pulmonary vascular pressures and rarely CNS excitation. Limited respiratory depression exists. Butorphanol is a potent analgesic agent with a favorable side effect profile.

Review and evaluation of the NCI/NTP carcinogenesis bioassays.

A comparison of the carcinogenesis bioassay results obtained by the National Cancer Institute (NCI) and the National Toxicology Program (NTP) indicates that approximately one-half of the bioassays directed by both institutions were positive for carcinogenicity. The more recent 85 bioassays completed by NTP reveal a higher proportion of studies interpreted as demonstrating no evidence of carcinogenicity than represented in the initial 198 bioassays conducted by NCI. Of the 100 NCI bioassays that were not positive for carcinogenicity 3 (3%) were classified in the category of "no evidence for carcinogenicity in two animal species." Of the 43 NTP bioassays that were not positive for carcinogenicity 36 (84%) were placed in the category of "no carcinogenic effects." The reason for this shift from a 33:1 positive to negative ratio in the NCI bioassays to an approximately 1:1 ratio in the NTP bioassays appears to be a difference in interpretation of the adequacy of the testing. For example, 6 of the 36 NTP negative bioassays involved testing in only one species. Uniform criteria for concluding that a bioassay is negative must be developed and the results of all existing and future carcinogenesis bioassays must be interpreted with these exclusive criteria. Other bioassay problems are explored, including the incomplete validation of the carcinogenesis bioassay protocol by confirmatory results with positive and negative reference agents, the apparent lack of bioavailability data for some orally administered negative compounds, the continued use of mouse hepatic neoplasia as a single discriminating parameter, the variability in the inter- and intrastudy incidence of spontaneous tumors, and the continued reliance on the maximum tolerated dose.

Synthesis and evaluation of 1,omega-diaryl-l,omega-alkanediamines related to the fibrinolytic bis(tetrahydroisoquinolines) and bis(benzylamines).

Since the previously investigated bis(tetrahydroisoquinolines) 1 and bis(benzylamines) 2 may be classified as 1,omega-diaryl-1,omega-alkanediamines, it appeared worthwhile to examine this structural concept as a guideline for predicting significant fibrinolytic activity. The prototype bis compounds 7, 14, 15, and 29-31, which were synthesized for this purpose, incorporate such molecular modifications as replacement of the tetrahydroisoquinoline nuclei of series 1 with tetrahydrobenzazepine (7) and tetrahydropyridoindole (14-15) nuclei. The latter compounds, as well as 29-31 which possess features common to both series 1 and 2, showed good to moderate activity in the standard rat (ip) screen. Significant departures from the 1,omega-diaryl-1,omega-alkanediamine structural concept led to compounds (35 and 40) of weak to moderate activity.