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.     

Coronary bypass surgery in 1971-80 and 1995-96: increased age and comorbidity,unchanged survival rates and fewer early reoperations 1 and 5 years postoperatively

OBJECTIVE: To describe the characteristics of patients undergoing coronary bypass surgery (CABG) over the past 30 years and the outcome after 1 and 5 years. DESIGN: Retrospective. METHOD: All 1041 patients who had undergone a first CABG in the Thorax centre of the Erasmus Medical Centre in Rotterdam during the period from 1 July 1971 through 31 May 1980 (group I) were compared with all patients who had also undergone such a first operation during the period between 1 September 1995 and 31 December 1996 (group II). Data on the patients, the operations, any reoperations and the mortality were obtained from patient records, from general practitioners and from municipal archives. Cumulative percentages of survival and of not having reCABG or percutaneous transluminal coronary angioplasty (PTCA) were analysed by using the Kaplan-Meier-method. RESULTS: The patients in group I were 11 years younger on average than those in group II and there were more men (group I: 88%, group II: 76%). The patients in group II had more comorbidity than those in group I. The actuarial perioperative mortality was 1.2% in group I and 1.6% in group II. The overall 5-year mortality was significantly lower in group I than in group II (9.1% vs. 11.0%). After adjustment for the baseline characteristics, however, the patients in group II had a lower risk of mortality. Coronary revascularisation in the first 5 years was required more often in group I than in group II (7.4% vs. 4.2%). Independent predictors of a higher 5-year mortality were: a reduced ejection fraction (both groups), more extensive vascular disease (group I), chronic pulmonary disease, renal function disorders and diabetes mellitus (all group II), while treatment for hyperlipidaemia had a favourable effect on survival. CONCLUSION: The age and comorbidity of the operated patients had increased over the years, while the chance of survival was no less than before and there was less chance of an early reoperation.     

The application of electric heart assist devices in 3 patients with end-stage heart failure as a bridge to transplantation

Left-ventricular assist devices have already gained an international place in the treatment of end-stage heart failure. It is expected that in future they will be increasingly used as a temporary bridging following the recovery from heart failure and to a lesser extent as a bridge to heart transplantation. Three patients with end-stage heart failure, men aged 68, 57 and 49 years, received a left-ventricular assist device (LVAD) as a bridge to transplantation. The device chosen was a Heartmate Vented Electric System (ThermoCardiosystems; Woburn, Massachusetts, US). In this system a pump is implanted under the diaphragm and connected to the apex of the left ventricle and the pars ascendens aortae. The first two patients reached the time of transplantation and used the LVAD for 367 and 416 days respectively. The third patient died after the pump had been implanted, due to progressive right-ventricle failure. The first patient died shortly after the heart transplantation.     

Stimulation of both humoral and cellular immune responses to HIV-1 gp120 by interleukin-12 in Rhesus macaques

The adjuvant effect of recombinant Rhesus macaque interleukin-12 (RhIL-12) on the induction of cellular and humoral immune responses elicited by the HIV-1 subunit vaccine protein gp120 in Rhesus macaques was examined. RhIL-12 in conjunction with gp120 was given at day 0, 28 and 84 intramuscularly. Coadministration resulted in an approximate 10-fold increase in plasma anti-gp120 antibody levels as compared to levels generated in control monkeys receiving gp120 alone. Potentiation of the humoral arm of the immune response was evident by both ELISA and an antiviral bioassay. In addition, RhIL-12 was found to produce a significant increase in gp120-specific proliferative responses and in the frequency of antigen-specific IFN-gamma and IL-2 producing T cells after restimulation of PBMC with gp120 in vitro indicating that RhIL-12 potentiates cell-mediated immune responses as well. A critical finding was that during the course of the study, RhIL-12 did not induce a neutralizing antibody response to the administered cytokine. The doses of RhIL-12 were well tolerated and no detectable adverse side-effects on hematopoietic and hepatic parameters were noted. The data revealed that IL-12, when coadministered intramuscularly, acts as a potent adjuvant which is able to enhance not only cellular but also humoral immune responses to gp120 in non-human primates and may have to be considered in future HIV vaccine strategies.     

巫山淫羊藿的化学研究

从小檗科Berberidaceae淫羊藿属Epimedium植物巫山淫羊藿Epimedium wushanense T.S.Ying的地上部分中分得两种黄酮甙单体,经理化性质鉴定及紫外、红外、质谱、氢谱、碳谱等光谱分析,确定甙Ⅰ是新化合物,命名为巫山淫羊藿甙(wushanicariin)。甙Ⅱ是已知化合物淫羊藿甙(icariin),系首次从该种植物中分离。