Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion

1. Imidazoline α₂-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α₂-adrenoceptor antagonism is involved.
2. Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
3. Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α₂-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective.
4. In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
5. Incubation of rat islets under conditions designed to minimize the extent of α₂-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion.
6. The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site leads to selective enhancement of sulphonylurea-induced insulin release.

     

Flow cytometry: Potential utility in monitoring drug effects in breast cancer

Summary Flow cytometric analysis of DNA ploidy and S-phase fraction are well recognized prognostic indicators in breast cancer. The present paper deals with the widening of the applications of flow cytometry to monitoring the effectiveness of antiestrogen therapy, detecting clonal selection and emergence of drug resistance, and monitoring chemosensitizing properties of drugs. Antiestrogen activity can be studied by DNA flow cytometry to address clinical research problems such as patient-specific pharmacokinetics, dosing compliance, and acquired antiestrogen resistance. Patient plasma specimens containing various concentrations of triphenylethylenes can be monitored for drug-induced effects using cell cycle measurements and correlated toin vivo drug levels. DNA flow cytometry has also been instrumental in the study of the effects of prolonged low-dose (0.5 µM for > 100 days) tamoxifen treatment on human estrogen receptor negative MDA-MB-231 cells, where it was shown that tamoxifen may significantly alter cell cycle kinetics and tumorigenicity of these cells, selecting a new, more aggressive, and rapidly growing clone. Lastly, it has been shown that the chemosensitizing properties of another triphenylethylene antiestrogen, toremifene, on estrogen receptor negative, multidrug resistant MDA-MB-231-A1 human breast cancer cells can be studied using flow cytometric analysis. Toremifene (and its metabolites N-desmethyltoremifene and toremifene IV) are able to resensitize MDA-MB-231-A1 cells to vinblastine and doxorubicin, as reflected in a marked shift of cells to G₂/M phase of the cell cycle. Flow cytometry is a widely available technique that might be applied clinically to monitor, at the cellular level, drug effects on tumors, including the modulators of drug resistance.     

Hospitals: to the next millennium

Hospitals are changing. Throughout the OECD the hospital, that enduring and pervasive organization which has delivered the vast majority of acute care services for decades, is being reconceptualized. We briefly analyse trends which clearly indicate that the existing concept of the hospital is rapidly coming to an end. The emerging model consists of a core facility comprising only the most acute services, intensive care, operating theatres and an accident and emergency unit, with all other services and units linked by information technology to each other and to the core facility. We explore some of the management challenges confronting those who will be responsible for taking their organization through the transition to the boundaryless hospital arrangement, discuss a number of the existing problems with today's hospitals which the new model has the propensity to resolve, and deal with some of the emerging issues which it brings with it.     

Assessment of myocardial viability by dynamic tomographic iodine 123 iodophenylpentadecanoic acid imaging: Comparison with rest-redistribution thallium 201 imaging

Background

This study examined the ability of dynamic ¹²³I-labeled iodophenylpentade-canoic acid (IPPA) imaging to detect myocardial viability in patients with left ventricular (LV) dysfunction caused by coronary artery disease.

Methods and Results

Serial 180-degree single-photon emission computed tomographic (SPECT) images (five sets, 8 minutes each) were obtained starting 4 minutes after injection of 2 to 6 mCi ¹²³I at rest in 21 patients with LV dysfunction (ejection fraction [EF] 34%±11%). The segmental uptake was compared with that of rest-redistribution ²⁰¹Tl images (20 segments/study). The number of perfusion defects (reversible and fixed) was similar by IPPA and thallium (11±5 vs 10±5 segments/patient; difference not significant). There was agreement between IPPA and thallium for presence or absence (κ=0.78±0.03) and nature (reversible, mild fixed, or severe fixed) of perfusion defects (κ=0.54±0.04). However, there were more reversible IPPA defects than reversible thallium defects (7±4 vs 3±4 segments/patient; p=0.001). In 14 patients the EF (by gated pool imaging) improved after coronary revascularization from 33%±11% to 39%±12% (p=0.002). The number of reversible IPPA defects was greater in the seven patients who had improvement in EF than in the patients without such improvement (10±4 vs 5±4 segments/patient; p=0.075).

Conclusions

¹²³I-labeled IPPA SPECT imaging is a promising new technique for assessment of viability. Reversible defects predict recovery of LV dysfunction after coronary revascularization.     

Coronary Health Issues for Lesbians

Since coronary heart disease (CHD) is the leading cause of death in American women it is therefore likely the leading cause of death among lesbians. Prevention of CHD is a major health issue for lesbians. Efforts must continue to empower all lesbians to take personal preventative action to prevent CHD. Women in general do not believe they are at risk for CHD. A common misperception is that CHD is a man's disease and the most likely threat to a woman's life is breast cancer. This misperception probably exists among lesbians as well. Over a lifetime, a woman is 10 times more likely to develop CHD than she is breast cancer. Breast cancer remains an important health concern for woman, but CHD risk must be addressed with potent educational and advocacy programs for the health of our communities. Prevention of the clinical manifestations of CHD hinges upon the prevention of plaque formation. It is an obligation of primary care providers to give advice regarding the prevention of plaque formation and therefore the prevention of subsequent CHD events and to collaborate with patients to address these issues in an individually tailored manner. This review addresses risk factors for CHD in lesbians to assist providers in achievement of that goal.     

Systematic Differences in Validity of Self-Reported Mammography Behavior: A Problem for Intergroup Comparisons?

Background. Prior studies of recall accuracy for screening mammogram behavior have examined relatively homogeneous groups. Data are limited on possible systematic group differences, so we evaluated women's recall accuracy in two separate care systems in one city.Methods. Women 50 to 70 years old with and without screening mammograms 10 to 14 months prior were identified from fiscal, clinic, and radiology records at a military care system (MCS) and a county-funded system (CFS) for indigents. Mammogram status was verified through radiology records. Women were excluded if mammograms were diagnostic, done for other than annual screening, or had abnormal results. Interview ers blinded to mammogram status surveyed randomly selected eligible women.Results. For 62 screened/31 unscreened MCS women and 78 screened/61 unscreened CFS women, specificity was similar, at 65 and 62%, respectively. In contrast, sensitivity varied significantly: 95% versus 79% (P = 0.011). Primary ethonocultural groups were Euro-American (MCS—60%) and Mexican American (CFS—85%). Although not different in specificity of recall (67% versus 61%), these major subgroups significantly differed in sensitivity (97% versus 80%, P = 0.017), proportion of true negatives due to never having a mammogram (35% versus 57%, P = 0.003), and proportion with ≥high school education (78% versus 19%, P < 0.00001).Conclusion. Systematic differences in recall validity may exist and compromise the accuracy of intergroup comparisons.     

Empowerment and the performance of health services

Addresses the issue of empowerment and its possible role in promoting the effectiveness of health services. Empowerment represents the ability of people within organisations to use their own initiative to further organisational interests. However, despite its apparent simplicity, the concept turns out to be quite complex and to have unanticipated implications. We explore some of these implications in health service organisations, and their consequences for health policy. Our conclusion is that many health policies may well act to degrade the empowerment of health service workers, and hence the performance of health service organisations.     

Selective impairment in the recognition of anger induced by diazepam

Rationale: Facial expressions appear to be processed by at least partially separable neuro-cognitive systems. Given this functional specialisation of expression processing, it is plausible that these neurocognitive systems may also be dissociable pharmacologically. Objective: The present study therefore compared the effects of diazepam (15 mg) with placebo upon the ability to recognise emotional expressions. Methods: A double blind, independent group design was used to compare the effects of diazepam and matched placebo in32 healthy volunteers. Participants were presented morphed facial expression stimuli following a paradigm developed for use with patients with brain damage and asked to name one of the six basic emotions (sadness, happiness, anger, disgust, fear and surprise). Results: Diazepam selectively impaired subjects’ ability to recognise angry expressions but did not affect recognition of any other emotional expression. Conclusions: The findings are interpreted as providing further support for the suggestion that there are dissociable systems responsible for processing emotional expressions. It is suggested that these findings may have implications for understanding paradoxical aggression sometimes elicited by benzodiazepines. Received: 27 May 1999 / Accepted: 7 July 1999     

The anaesthetic management of a patient with Emery-Dreifuss muscular dystrophy

Purpose

This case report presents a patient with Emery-Dreifuss Muscular Dystrophy and describes the anaesthetic considerations.

Clinical features

The features of Emery-Dreifuss Muscular Dystrophy are contractures, humeroperoneal muscle weakness and cardiomyopathy. The anaesthetic considerations for this syndrome are difficult tracheal intubation, difficult spinal anaesthetic, heart block, gastric reflux, rhabdomyolysis, and unproved malignant hyperthermia susceptibility.

Conclusion

The major anaesthetic problem for the patient with Emery-Dreifuss Muscular Dystrophy could be a life-threatening cardiomyopathy.