Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(1-(α-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4- tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca²⁺-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca²⁺-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 μM) shifted the EC₅₀ of Ca²⁺ for contractile activation of skinned fibers of pig heart from 2.41 μM to 0.73 μM, whereas [-]-EMD 60264 (30 μM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35 % of pre-drug control with [+]-EMD 60263 in comparison to 113 % with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component I_Kr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define I_Kr. It is concluded, that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca²⁺-sensitizing effect. The accompanying prolongation in action potential duration is caused by block of the I_Kr component of the delayed rectifier. While the inotropic effects are stereoselective, most of the electrophysiological actions are clearly independent of sterical configuration. The combination of Ca²⁺-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic use. Received: 7 January 1997 / Accepted: 25 February 1997     

Induced luteolysis in the primate: rapid loss of luteinizing hormone receptors

The molecular mechanisms involved in luteolysis are still unclear in the primate. This study aimed to investigate the effect of induced luteolysis on the ovarian luteinizing hormone (LH) receptor and the steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset monkey. Luteolysis was induced in the mid-luteal phase either directly by systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal using systemic gonadotrophin releasing hormone antagonist (GnRHant) treatment. The LH receptor was studied by isotopic mRNA in-situ hybridization and in-situ ligand binding and 3beta-HSD expression was studied using isotopic mRNA in-situ hybridization and immunohistochemistry. Induced luteolysis was associated with a reduction in the expression of LH receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a reduction in the LH receptor (P < 0.05) and 3beta-HSD protein concentrations within 24 h. There were no differences in the findings whether luteolysis was induced with PGF2alpha or GnRHant. This study shows that disparate mechanisms to induce luteolysis in the primate result in an identical rapid loss of the LH receptor and 3beta-HSD. In conclusion, induced luteolysis leads to rapid loss of the steroidogenic pathway in luteal cells.      

Complementary medicine: are patients' expectations being met by their general practitioners?

Complementary, or alternative, medicine has increased in popularity among patients during the past 20 years. The purpose of this study was to determine whether general practitioners met their patients' expectations with regard to complementary medicine. In a postal survey all 71 accredited general practitioners in the district of Kassel, Germany, received a structured questionnaire about their experience with complementary medicine. Forty (56%) replied. In 10 of these practices 310 patients were interviewed about their attitudes towards and expectations of such treatment. Of the responding doctors 95% used, at least occasionally, some form of complementary medicine (most commonly herbal medicine, neural therapy or homeopathy). All but three patients accepted the value of complementary medicine, 58% of them (especially younger, more highly educated patients and those from rural practices) preferred it to orthodox medicine and 40% of the patients had received some form of complementary therapy. Nearly 70% of the patients requested that complementary medicine be practised by their general practitioner more frequently than at present. There was no significant link between patient satisfaction with the doctor and patients' view of, or demand for, complementary medicine. Although both patients and practitioners were interested in complementary therapy, there was a gap between the willingness, or the ability, of general practitioners to use complementary medicine and the patients' demand for these alternative forms of treatment.     

Semen parameters and testicular pathology in men with testicular cancer and contralateral carcinoma in situ or bilateral testicular malignancies

We evaluated 14 patients with bilateral testicular tumour, one-sided tumour and contralateral carcinoma in situ (CIS) of the testis or testis tumour in single testis with respect to their fertility. We analysed semen parameters, serum hormones [follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone], testicular sonography, testicular volumes and testicular histology prior to further anti-cancer treatment. Ten out of 14 patients showed normal or reduced sperm concentrations, while 4/14 patients were azoospermic. Serum FSH levels showed a significant negative correlation with sperm concentrations in patients with testicular malignancies (r = -0.64, P = 0.025). Testicular volumes revealed a significant positive correlation with semen parameters in patients with testes that were affected by CIS (r = 0.733, P = 0.038). We conclude that even bilateral testicular cancer and/or CIS do not preclude fertility and, therefore, patients should be offered andrological investigation and therapy, including possibly surveillance strategy or the chance for cryopreservation of the semen prior to further treatment in order to preserve their chances for paternity.      

How do academic heads of departments of general practice organize patient care? A European survey.

BACKGROUND. Compared with other clinical disciplines, academic general practice is in a difficult situation with respect to patient care. There are at least three different possible models of working arrangements for heads of departments of general practice: to work in a surgery in a medical school; to work in a surgery in the community, separate from a part-time university post; or to work part-time in a surgery in the community, separate from a university post. AIM. A study was undertaken to explore these models and to gain an understanding of academic teachers' organization of patient care in Europe. METHOD. A total of 77 heads of departments in universities in 12 European countries were sent a questionnaire enquiring about important characteristics of their department, the number of patients they treated per week and how they allocated their time. RESULTS. Sixty nine heads of department (90%) responded. Of respondents, 55% worked part-time in a surgery, separate from a university post, nearly one third worked mainly in a surgery, separate from a part-time university post, and 16% worked in a surgery in a medical school. Those working in a surgery with only a part-time university post spent most time in patient care compared with those working in other models (mean of 57%). Respondents working in a surgery in a medical school spent most time on administration (34%); they spent 22% of their time on patient care and 20% on education. Respondents working in a surgery in a medical school spent 25% of their time on research, those working in a surgery separate from a part-time university post spent 12% of their time on research, and those working mainly in a university with a part-time practice post spent 24% of their time on research. Those working mainly in a university post spent only 17% of their time in patient care. CONCLUSION. Working in a surgery in a medical school represented a well-balanced model of time allocation between patient care, research and education and seemed to be a good approach for the integration of general practice into medical schools. Working part-time in a surgery with a university post is an appropriate model for academic integration, but patient care seemed to be neglected. Those doctors working mainly in the community with a part-time university post were able to provide continuity of care and to come into close contact with the everyday problems of general practitioners. However, they might have to struggle for academic recognition.