Glutathione conjugates and their synthetic derivatives as inhibitors of glutathione-dependent enzymes involved in cancer and drug resistance

Alterations in levels of glutathione (GSH) and glutathione-dependent enzymes have been implicated in cancer and multidrug resistance of tumor cells. The activity of a number of these, the multidrug resistance-associated protein 1, glutathione S-transferase, DNA-dependent protein kinase, glyoxalase I, and gamma-glutamyl transpeptidase, can be inhibited by GSH-conjugates and synthetic analogs thereof. In this review we focus on the function of these enzymes and carriers in cancer and anti-cancer drug resistance, in relation to their inhibition by GSH-conjugate analogs.     

Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries

Donitriptan is a potent, high efficacy agonist at 5-HT(1B/1D) receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E(max): 103+/-8% and 110+/-12%, respectively), but the potency of donitriptan (pEC(50): 9.07+/-0.14) was significantly higher than that of sumatriptan (pEC(50): 7.41+/-0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E(max): 29+/-6%) than sumatriptan (E(max): 14+/-2%; pEC(50): 5.71+/-0.16), yielding two distinct pEC(50) values (8.25+/-0.16 and 5.60+/-0.24). Incubation with the 5-HT(2) receptor antagonist ketanserin (10 microM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E(max) and pEC(50) were 9+/-2% and 7.33+/-0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C(max)) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9+/-1.5% and 3.8+/-2.0%, respectively; these are not different from those by C(max) concentrations of sumatriptan (1.7+/-0.4% or 2.2+/-0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.     

Averaged electrode voltages in users of the Clarion cochlear implant device

Averaged electrode voltages (AEVs) are of secondary importance for integrity testing of cochlear implant devices featuring back-telemetry. However, AEVs are device-independent and may show intermittent failures and deviant stimulation patterns unnoticed by telemetry. We collected AEVs from 18 users of the Clarion 1.2 system and 6 users of the HiFocus system in order to establish norms for evaluating AEVs in difficult cases. The stimuli were presented with the standard clinical software. Monopolar stimulation at about 16 microA showed large AEVs (mean, 173 microV) suitable for integrity testing. No electrode failures were found. The AEV amplitudes from neighboring electrodes differed by less than 30% (2 SD). The AEVs from subjects with the Clarion HiFocus electrode and/or the Clarion electrode positioner were within the normal range. The AEV amplitudes from bipolar stimulation were much more variable. Inversion of phases between electrodes was found in patients with an altered state of the cochlea (otosclerosis and osteogenesis imperfecta) and in a patient with a curled electrode tip. There was no correlation across subjects between AEVs and electrode impedances. Therefore, impedances are dominated by the electrode-tissue interface, in contrast to AEVs, which are determined by the volume conduction in the body.     

Remifentanil-sevoflurane anaesthesia for laparoscopic cholecystectomy: comparison of three dose regimens

The objective of this study was to determine a dosing regimen for remifentanil-sevoflurane anaesthesia that achieves an optimal balance between quality of anaesthesia and time to recovery. Patients undergoing elective laparoscopic cholecystectomy were randomly allocated to receive 0.4, 0.8 or 1.2 MAC (minimal alveolar concentration) of sevoflurane combined with remifentanil as required to maintain stable anaesthesia. For induction of anaesthesia, the remifentanil dose was 25 microg x kg(-1) x h(-1) and the mean propofol dose which was required to obtain loss of consciousness was 1.59 mg x kg(-1). During the maintenance phase, the mean remifentanil dose was 16.0, 14.1 and 13.0 microg x kg(-1) x h(-1) for the 0.4, 0.8 and 1.2 MAC groups, respectively. The mean sevoflurane maintenance dose was 0.91, 1.24 and 2.1% end-tidal for the 0.4, 0.8 and 1.2 MAC groups, respectively. The incidence of somatic responses was significantly higher in the 0.4 MAC sevoflurane group. Recovery times were significantly faster in the 0.4 compared to the 0.8 and 1.2 MAC groups and in the 0.8 compared to the 1.2 MAC group. The combination of 14 microg x kg(-1) x h(-1) remifentanil and 1.24% end-tidal sevoflurane achieved the optimal balance between the quality, and recovery from anaesthesia.     

Personality pathology and treatment outcome in major depression: a review

OBJECTIVE: A longstanding belief among many clinicians is that patients with depression and comorbid personality pathology have a worse response to standard depression treatment. This presents potentially significant treatment implications, since personality pathology in depressed patients appears to be common. METHOD: PsycINFO and MEDLINE were systematically searched for studies relating personality to treatment outcome. Over 50 studies were obtained and grouped according to the method used to assess personality pathology. RESULTS: High neuroticism scores generally predicted worse outcome, especially over long-term follow-up. Tridimensional Personality Questionnaire scores did not have a consistent relationship to treatment outcome despite some promising initial findings. Most studies involved patients with comorbid personality disorders; these studies produced conflicting results. Other measures of personality pathology produced an array of findings ranging from a moderately worse outcome to no difference. CONCLUSIONS: Whether or not personality pathology significantly worsens outcome in patients with major depression appears to depend on study design, since the rate of personality pathology varies markedly depending on how it is measured. In addition, depressed patients with personality pathology appear less likely to receive adequate treatment in uncontrolled studies. Finally, studies rarely control for depression characteristics (e.g., chronicity, severity) that may influence outcome and be related to personality pathology. Overall, the best-designed studies reported the least effect of personality pathology on depression treatment outcome. Clinically, this suggests that comorbid personality pathology should not be seen as an impediment to good treatment response.     

Melancholia: definitions,risk factors,personality, neuroendocrine markers and differential antidepressant response

OBJECTIVE: To evaluate the CORE measure of melancholia, against the DSM-IV construct of melancholia. To evaluate the validity of both the CORE and DSM-IV constructs of melancholia against psychosocial risk factors, anxiety and personality disorder comorbidity, neuroendocrine markers and differential anti depressant response to fluoxetine and nortriptyline. METHOD: One hundred and ninety-five outpatients with major depression were evaluated for melancholia with both the DSM-IV criteria and the CORE evaluation. Both constructs were evaluated for validity against psychosocial risk factors, comorbidity, biological markers and differential antidepressant response. RESULTS: The CORE measure has satisfactory interrater reliability when used dimensionally, but has unacceptably low agreement for making a categorical diagnosis of melancholia. There is remarkably poor agreement (kappa = 0.11) between the CORE and DSM-IV criteria for melancholia. Neither the DSM-IV nor CORE criteria for melancholia identified subgroups of patients with better childhood environments or less anxiety or personality disorder comorbidity.The CORE criteria for melancholia, but not DSM-IV, identified patients with neuroendocrine disturbance. CORE scores also were associated with differential responses to fluoxetine and nortriptyline, but not in anticipated directions. Thus, high CORE scores were associated with a higher recovery rate with fluoxetine than nortriptyline. CONCLUSION: While the episode specifier of melancholia should be retained in diagnostic systems, the DSM-IV criteria were not validated against any of the variables examined in this study.The CORE construct of melancholia, was validated against neuroendocrine measures, and was associated with a differential antidepressant response. However, the limits imposed by interrater reliability,suggest the CORE measure should be used dimensionally and not to make a categorical diagnosis of melancholia.     

Patterns and predictors of remission,response and recovery in major depression treated with fluoxetine or nortriptyline

OBJECTIVE: The first objective of this paper was to describe the pattern of remission, response and recovery in patients with major depression who were randomised for treatment with fluoxetine ornortriptyline. The second objective was to report on the demographic and diagnostic predictors of the response and recovery in these depressed patients. METHOD: One hundred and ninety-five patients with major depression were recruited for this outpatient study. After a detailed clinical and neurobiological evaluation patients were randomized to receive either fluoxetine or nortiptyline as an initial antidepressant treatment. RESULTS: Of the 195 depressed patients randomised to treatment,154 completed an adequate 6-week trial of either fluoxetine or nortriptyline as their initial antidepressant. Of the 41 patients who did not complete an adequate trial the dropout rate was higher on those randomized to nortriptyline (p = 0.02). There was also an important interaction of drug and gender in determining dropouts in that women did not complete an adequate trial with nortriptyline and men did not complete an adequate trial with fluoxetine (p = 0.002).Of the 154 patients who completed an adequate 6-week antidepressant trial there were no significant differences in 6-week measures of depression severity or of percentage improvement. However, if we use an intention to treat analysis and dichotomise outcomes into response,remission or recovery; then recovery rates were significantly higher with fluoxetine than nortriptyline (p = 0.005).Using an intention to treat analysis fluoxetine was superior tonortriptyline in women, in those less than 25-years old, and in those with atypical depression. Independent of drug, those with chronic depressions had a poorer outcome. CONCLUSION: In this sample of depressed patients randomized tonortriptyline or fluoxetine the change in depressive symptoms over 6 weeks were comparable between fluoxetine and nortriptyline. However,when we look at the more clinically important variable of recovery then fluoxetine was superior to nortriptyline. Predictors of a poorer response to nortriptyline were gender, young age and atypical depression.The results challenge traditional beliefs that selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressant have comparable efficacy.