This study was undertaken to investigate pharmacological variables that influence the reinforcing efficacy of psychostimulants. Rhesus monkeys (n = 9) responded under a within-session, exponentially increasing, progressive ratio schedule of cocaine reinforcement. Doses of cocaine, methylphenidate (MP), cocaine analogs [(±)-2β-propanoyl-3β-(2-naphthyl)-tropane (WF-23), HD-23; (±)-2β-propanoyl-3β-(2-isopropenyl)tropane (WF-60), HD-60; and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), and 2β-propanoyl-3β-(4-tolyl)-tropane (HD-11, WF-11), PTT], and MP analogs [(αR,2R)-α-(2-naphthalenyl)-2-piperidineacetic acid methyl ester, HDMP-28; and (αR,2S)-α-(2-naphthalenyl)-2-pyrrolideneacetic acid methyl ester, HDMP-29] that varied in their pharmacokinetic and pharmacodynamic properties were substituted for cocaine. These drugs were chosen according to their selectivity for dopamine transporters (DAT) and 5-hydroxytryptamine (serotonin) transporters (5-HTT) as assessed in rodents and their duration of action. In addition, data pertaining to the rate of onset at DAT were collected for the cocaine analogs using an ex vivo binding assay in rodent tissue. Finally, the pharmacodynamic profile of select drugs was confirmed in primate brain tissue. All drugs had reinforcing effects except HDMP-29. The rank ordering of the peak breaking points (BPs) was cocaine = MP = HDMP-28 ≥ HD-60 ≥ PTT ≥ HD-23 > HDMP-29. The time to peak DAT occupancy for the cocaine analogs was greater than 30 min. The potency to maintain peak BP was significantly correlated with DAT affinity. There was not a linear relationship between monoamine transporter affinity and reinforcing efficacy, but it appeared that in nonhuman primates there is a range of DAT affinity under which maximal responding is maintained. Interestingly, the 5-HTT-selective cocaine analog HD-60 functioned robustly as a reinforcer at several doses in all monkeys tested. These data question the dogma regarding the role of pharmacokinetic factors and the relative influence of DAT and 5-HTT in stimulant reinforcement.
Migraine occurring at menstruation is frequently difficult to treat. A 38-year-old woman with exceptionally severe menstrual migraine was treated by temporary ovarian suppression using Zoladex, a long acting luteinizing hormone-releasing hormone agonist. There was prompt relief of headache, and after several months of treatment the patient elected to undergo surgical oophorectomy with subsequent resolution of her migraine. A trial of reversible hypogonadism using an LHRH agonist may thus be helpful in predicting the result of surgical castration in this situation.
CorrectionImportance of hypovolaemic shock and endoscopic signs in predicting recurrent haemorrhage from peptic ulceration: a prospective evaluation Three errors occurred in this paper by P C Bornman et al (27 July, p 245).In table I the number of rebleeds in patients with endoscopic signs of a clot should have read 12 (25) not 11 (23).In table II the value 112 under "No endoscopic sign, black spots" should have read 86, and the remaining 26 patients should have been tabulated under "Endoscopic sign, no rebleed.
EDITORIAL COMMENT: The importance of postmenopausal symptoms and whether or not they can be safely controlled is undeniable — the 3 main considerations are patient compliance, complications and cost. This paper shows that transdermal administration of oestradiol was a clear winner in comparison with oral ethinyl oestradiol, although the important entity of osteoporosis was not addressed in this study. The findings reported in this paper are of more than academic interest; the trial warrants verification with a larger number of patients, and other oral oestrogen preparations (oestriol, oestrone, oestradiol) should be compared with transdermal and subcutaneous oestradiol therapy. We will be pleased to publish the findings of such studies in this journal. The pattern of uterine bleeding with different treatment regimens warrants careful documentation, since the return of menstruation is often the reason patients give for discontinuation of hormone replacement therapy. Summary: A double blind crossover study of transdermal oestradiol (50ug/ day) and ethinyl oestradiol (20ug/day) was conducted with 25 postmenopausal women. Transdermal oestradiol increased circulating levels of oestradiol and oestrone. Both preparations favourably improved patients' symptoms and vaginal cytology, lowered gonadotrophin levels and urinary calcium loss and gave a satisfactory menstrual pattern, Transdermal oestradiol had no effect on measures of hepatic function whereas oral ethinyl oestradiol significantly altered levels of sex hormone binding globulin, plasma renin substrate and lipoproteins. Transdermal oestradiol has a comparable beneficial effect on postmenopausal symptoms to ethinyl oestradiol without the adverse effects on hepatic proteins.
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