Danazol administration after gonadotrophin-releasing hormone analogue reduces rebound of uterine myomas [published erratum appears in Hum Reprod 1998 Mar;13(3):780]

We report the results of administration of danazol after suspension of gonadotrophin-releasing hormone analogue (GnRHa) therapy for uterine myomas. A total of 21 women with uterine myomas was treated with 100 mg danazol for 6 months after GnRHa therapy. Uterine volume and endocrine status were monitored monthly by ultrasound and assay of plasma gonadotrophins, oestradiol and progesterone. The results show a rebound of uterine volume about 30% less than in controls at the end of danazol therapy. Menstrual cyclicity returned after 65 +/- 3 days in 16 subjects and five patients remained amenorrhoeic. Hormone assays confirmed renewed ovarian function in the women whose menstrual periods returned. Bone mineral content was substantially reduced during GnRHa treatment but improved significantly during danazol therapy even in the women who remained amenorrhoeic. These results show the utility of danazol in prolonging the therapeutic effects of GnRHa. The mechanism by which danazol inhibits rebound of uterine volume may be due to its antiprogesterone effects on uterine myomas.      

Pneumothorax and other lung diseases: effect of altered resolution and edge enhancement on diagnosis with digitized radiographs

Prior studies have shown that pneumothorax is one of the more difficult entities to diagnose with digitized radiography. This study was designed to test whether increasing resolution from 1.25 to 2.5 line pairs per millimeter (lp/mm) and image processing (edge enhancement from unsharp masking) would increase accuracy and confidence in the diagnosis of pneumothorax, as well as normal cases and other forms of lung disease. Conventional radiographs were digitized with use of a laser reader and then reformatted as film hard copy. Eleven observers read 35 cases reformatted in three different ways (1.25 lp/mm, 2.5 lp/mm, 1.25 lp/mm unsharp mask). The images with finer resolution (2.5 lp/mm) and unsharp mask images were superior to those with coarser resolution (1.25 lp/mm) for the diagnosis of pneumothorax. There was no difference in diagnostic accuracy for normal patients. For abnormalities other than pneumothorax, the unsharp mask images were significantly worse. Confidence in the diagnosis of pneumothorax and other abnormalities was highest with the finest resolution (2.5 lp/mm).     

Characterization of antibody and selection of alternative drug therapy in hydrochlorothiazide-induced immune hemolytic anemia

The authors report the clinical and laboratory findings of a patient who had severe immune hemolytic anemia due to hydrochlorothiazide (HCTZ). In this case, the HCTZ antibody reacted not only with other thiazide and thiazide-like drugs, but also with a chemically unrelated diuretic, ethacrynic acid. These results indicate that HCTZ antibody activity is not restricted solely to the thiazides and imply that therapy with any of the reactive drugs would be contraindicated for this patient. The serologic screening for drug reactivity may be useful for selecting alternative therapy for patients with drug-induced immune hemolytic anemia.     

Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

Discrimination of a drug mixture in rats: role of training dose, and specificity

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.     

Temporal factors in drug discrimination: Experiments with nicotine

The role of the presession interval (PI) in drug discrimination research has been studied in rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure. Different groups of rats were trained at different Pls, varying between 5 and 35 min, and tests were then carried out for qualitative and quantitative differences between the cues. There was complete generalization from nicotine cues trained at one time to tests carried out at other times. The sensitivity of the cues at different Pls to the nicotinic antagonist mecamylamine was very similar. Generalization to amphetamine was nearly complete when the nicotine cue was established with PI of 20-35 min and only partial when the PI for the nicotine was 5 min. Thus, there was no clear evidence for any qualitative difference between nicotine cues established with different PIs. However, the PI influenced quantitative aspects of the nicotine cue in a marked and complex manner. Increasing the PI during training produced a two- to three-fold decrease in the ED(50), whereas increasing the PI during testing produced a two- to three-fold increase in the ED(50). This shows that the effects of changing the PIs during training and testing were similar in magnitude but opposite in direction. These changes in ED(50) values can be explained by pharmacokinetic considerations in conjunction with knowledge of the role of training dose in the discrimination of nicotine. The quantitative sensitivity of the drug discrimination procedure can be substantially influenced by the choice of temporal parameters used in training and testing.