A phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma.

OBJECTIVES: Gemcitabine and carboplatin each have demonstrated effectiveness without increased neurotoxicity in pretreated patients with ovarian cancer. We evaluated the efficacy and safety of gemcitabine plus carboplatin in patients with recurrent ovarian cancer in a multicenter phase II study. METHODS: Women with histologically proven measurable or evaluable epithelial ovarian cancer (any FIGO) who relapsed > or =6 months after discontinuation of first-line, platinum-containing therapy received gemcitabine 1000 mg/m(2) on days 1 and 8 and carboplatin AUC 4 on day 1 (after gemcitabine) every 21 days for up to six cycles. RESULTS: Of the 40 enrolled/evaluable patients, 6 (15%) had complete response and 19 (47.5%) had partial response (PR), including one patient with PR in nonmeasurable disease (PRNM), for an overall response rate of 62.5% (95% CI, 45.8-77.3%). The median duration of response was 7.8 months (95% CI, 6.7-10.0), the median time to progressive disease was 9.6 months (95% CI, 8.5-11.0), and the median time to treatment failure was 9.3 months (95% CI, 8.2-10.4). The main grade 3/4 toxicities were neutropenia (78% of patients), leukopenia (30%), thrombocytopenia (18%), and anemia (15%); no grade 4 nonhematologic toxicities occurred, and grade 3 nonhematologic toxicities were mild. CONCLUSIONS: The combination of gemcitabine and carboplatin is active and feasible in platinum-sensitive patients with recurrent ovarian cancer. This regimen is undergoing further evaluation in a large phase III trial.

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Chemotherapy for malignant pleural mesothelioma: past results and recent developments.

This review summarises the results of previously conducted clinical trials, and subsequently presents data arising from all phase II-III studies on chemotherapy of malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the antimetabolites, and in particular to pemetrexed that produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine-applied as a single agent or in combination with cisplatin-as well as vinorelbine appear to improve the quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. The publication of pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon establish a standard of care.

Gemcitabine in non-small cell lung cancer (NSCLC).

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has increased greatly in the past few years. While cytotoxic drugs are currently used both as single agents and in combination for palliation in locally advanced and metastatic disease, they have also been incorporated into multi-modality treatment strategies of Stage I to Stage III NSCLC. One of the main reasons for the increased acceptance of chemotherapy is the development of new substances. Among the most promising of these new drugs is the antimetabolite gemcitabine. Several single-arm gemcitabine Phase II studies involving more than 400 patients show validated response rates in more than 20% of the patients. These positive results have also been confirmed in randomized Phase II studies. Gemcitabine's unique mechanism of action, its lack of overlapping toxicity with other agents, and its favorable toxicity profile also define it as an ideal candidate for combination therapy. The activity seen with single-agent gemcitabine therapy can be compared with that of cisplatin-etoposide combination therapy. Gemcitabine-cisplatin combination response rates range from 31% to 54%, with a median survival time between 8.4 and 15.4 months and a 1-year survival rate between 30% and 59%. In addition to the clinical research of gemcitabine-cisplatin combinations, gemcitabine has also been tested in various double and triple combinations with carboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide. Investigations combining gemcitabine with radiation therapy are on-going. The following review will summarize results from representative Phase I/II and III studies using gemcitabine for NSCLC patients.

Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: a multicenter phase II trial.

BACKGROUND: To evaluate the activity of MTA plus cisplatin in chemotherapy-naive patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-six chemotherapy-naïve patients with NSCLC received 500 mg/m2 MTA plus 75 mg/m2 cisplatin every 21 days, with 4 mg dexamethasone orally twice daily on the day before, of, and after MTA administration. RESULTS: Median age was 58 years. WHO performance status was 0-2. Eighteen patients each had stage IIIB and IV disease. Seventeen patients each had squamous-cell and adenocarcinoma; two had undifferentiated disease. Fourteen patients (39%; 95% confidence interval: 23%-57%) showed partial response; seventeen (47%) had stable disease. Median survival was 10.9 months. Twenty-one patients (59%) experienced grade 3 or 4 granulocytopenia without fever or infection. Five (14%) and six (17%) patients experienced grade 3 anemia and grade 3 or 4 thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea in two patients (6%), and grade 3 and 4 diarrhea in one patient (3%) each. One patient each experienced grade 4 ALT and grade 3 bilirubin and AST elevations. CONCLUSIONS: MTA plus cisplatin is well tolerated and active against NSCLC. Further studies of this combination are warranted.

Gemcitabine in locally advanced and metastatic non-small cell lung cancer: the Central European phase II study.

The efficacy and toxicity profile of gemcitabine was evaluated in this phase II study of chemonaive patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). Eighty patients (62 males, 18 females) were entered into this study. The disease stage was IIIA in ten patients, IIIB in 32, and IV in 38 patients. The median age was 61 (range 41 - 78). Karnofsky performance status was > or = 80 in 88% of patients. All patients were chemonaive, but five patients had received prior radiotherapy and 34 patients had undergone prior surgery. Gemcitabine 1250 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Patients received up to nine cycles (median three cycles). Of 872 doses 815 (93%) were administered without dose delay or modification. Of the 80 patients enrolled, 76 were evaluable for efficacy analysis, and 16 patients had a partial response for an overall response rate of 21.1% (95% CI, 11.9-30.3%). A further 47 patients (61.8%) had stable disease. Partial responses were seen in eight of 41 stage III patients (19.5%) and in eight of 35 stage IV patients (22.9%). The median time to progressive disease was 4.6 months. Median survival for all 80 patients was 7.1 months. Haematological toxicity was mild with grade 3 4 neutropenia in 6.3% of patients, grade 3 thrombocytopenia in 3.8% of patients, and grade 3 anaemia in 2.5% of patients. Grade 3 non-laboratory toxicity was: somnolence (1.3% of patients), infection (1.3%), nausea and vomiting (6.4%) and dyspnoea (5.1%). This study confirms that single-agent gemcitabine is active in advanced NSCLC and its well-tolerated safety profile makes it particularly suited to outpatient use.

Effects of exercise on circulating vascular adhesion molecules in healthy men.

Based on previous studies showing an increase in circulating soluble intercellular adhesion molecule-1 (sICAM-1) after exercise, we hypothesized that exercise may also increase serum levels of the vascular cell adhesion molecule-1 (sVCAM-1) and sE-selection. In a prospective controlled clinical trial, serum levels of sE-selectin, sICAM-1 and sVAM-1 were measured before and after two different exercise protocols in healthy untrained men. Lactate levels increased up to 12.7 mmol/L (95% confidence interval: 10.1-15.9) and 3.6 mmol/L (CI: 2.4-4.7) after ergometry and after an one hour endurance exercise at 60% of the maximal work intensity, respectively (p = 0.028 vs baseline and controls). The maximal increase in lymphocyte counts of 106% (CI: 63-146), which was only of short duration, was higher immediately after ergometry as compared to that observed after endurance exercise (p = 0.028). However, the maximal increase in neutrophil counts of 178% (CI: 120-298) which was seen at 2 hours after endurance exercise was higher than that seen after ergometry (p = 0.028). In contrast, only small changes of circulating adhesion molecules were seen immediately after ergometry: sICAM-1 increased by 11% (CI: 4-25; p = 0.028), and similar tendencies were also observed for sVCAM-1 and sE-selectin. No other consistent and time-dependent changes of circulating adhesion molecules were observed and all differences and changes were < or = 11%. In sum our study provides evidence that recreational sporting activities in untrained healthy subjects at normal altitude have little influence on serum levels of the circulating vascular adhesion molecules sE-selectin, sVCAM-1 or sICAM-1.

Phase II trial of gemcitabine in advanced non-small-cell lung cancer.

Gemcitabine has shown activity in different solid tumors. In the present study we have evaluated its efficacy in 32 patients with advanced non-small-cell lung cancer in a phase II trial. Gemcitabine (1250 mg/m2) was given intravenously as a 30-minute infusion on days 1, 8 and 15. Cycles were repeated every 4 weeks. Twenty-nine patients were evaluable for response and all patients for toxicity. Partial remissions and stable disease were seen in 4 (14%) and 13 (45%) patients, respectively. Improvement of symptoms occurred in 54% of the patients. Side effects were mild and included predominantly leukopenia and thrombocytopenia. In conclusion, gemcitabine is active and well tolerated in patients with advanced non-small-cell lung cancer.

Characterization of angiotensin-II effects on cerebral and ocular circulation by noninvasive methods.

AIMS: The role of the renin-angiotensin-system (RAS) in the cerebral and ocular circulation is still a matter of controversy. In vitro and animal data lead to partially contradicting results. However, direct investigation of locally generated angiotensin II (Ang II) in humans is not possible in vivo. Hence, we hypothesised that it might be possible to characterize local effects of Ang II by comparing systemic and local haemodynamic parameters during exogenous Ang II infusion. METHODS: In a placebo-controlled, double-blind, two-way cross over study blood flow velocities in the middle cerebral and the ophthalmic artery and ocular fundus pulsations were measured during stepwise increasing doses of Ang II in 10 healthy subjects. Blood flow velocities were assessed by Doppler sonography, fundus pulsation amplitudes (FPA), which estimate local pulsatile ocular blood flow were measured by laser interferometry. Additionally, systemic blood pressure and pulse rate were measured. RESULTS: Ang II dose-dependently decreased resistive index (RI) and increased mean flow velocities (MFV) in both arteries. Fundus pulsation amplitude was dose-dependently decreased by Ang II, whereas mean arterial pressure (MAP) was significantly increased. Pulse pressure amplitude (PPA) was not affected by Ang II administration. There was a high degree of correlation between changes in RIs and the analogously calculated PPA/systolic blood pressure during Ang II infusion, which indicates that the changes in RI after Ang II administration can be attributed to changes in systemic haemodynamics. Calculation of total local ocular blood flow from fundus pulsation amplitudes and changes in flow pulsatility in the ophthalmic artery further argue against significant blood flow changes after Ang II administration. CONCLUSIONS: Interpretation of data from Doppler sonography and laser interferometry must be done very carefully when concomitant changes in systemic haemodynamics occur. RI cannot necessarily be taken as an index of distal vascular resistance in these cases and changes in MFV can be caused by changes in vessel diameter or in blood flow. Moreover, FPA cannot be taken as a measure of ocular blood flow if no additional data on flow pulsatility are available. The combination of our systemic and local haemodynamic data indicates that cerebral and ocular circulation are comparably insensitive to changes in local Ang II concentrations. Fundus pulsation and blood flow velocity measurements indicate that neither choroidal nor optic nerve head blood flow are significantly affected by administration of Ang II.

The effect of systemic nitric oxide-synthase inhibition on ocular fundus pulsations in man.

There is experimental evidence that endothelium derived nitric oxide is involved in the regulation of ocular vascular tone. The purpose of this study was to investigate the effects of NO-synthase inhibition by N-monomethyl-L-arginine (L-NMMA) on ocular fundus pulsations in young healthy volunteers. Three milligrams per kilograms L-NMMA were administered i.v. over 5 minutes. Protocol 1: Measurements of blood pressure, pulse rate, fundus pulsation amplitude, NO-exhalation, and cardiac output were performed at baseline and 10, 30, 60, 90, 150, and 300 minutes after L-NMMA infusion (n = 8). Fundus pulsation amplitude, which has been shown to estimate the pulsatile component of the choroidal blood flow, was recorded with a recently developed laser interferometer. Protocol 2: Measurements of blood pressure, pulse rate, fundus pulsation amplitude, NO-exhalation, and blood flow velocity in the ophthalmic artery were performed in a randomized, placebo controlled cross over study (n = 10). Ten minutes after L-NMMA administration fundus pulsation amplitude decreased by 23 +/- 2% (protocol 1) and 19 +/- 1% (protocol 2, P < 0.01 each), cardiac output by 12 +/- 2% (P < 0.01), and exhaled NO by 55 +/- 6% (protocol 1) and 41 +/- 6% (protocol 2, P < 0.01 each). All parameters returned to baseline values within the 300 minutes observation period, with a faster recovery of fundus pulsation amplitude than of cardiac output and exhaled NO. Blood pressure, pulse rate, and ophthalmic artery blood flow velocity showed only minor changes during and after administration of L-NMMA. Our results suggest that systemic NO-synthase inhibition reduces pulsatile choroidal and most likely total choroidal blood flow in humans. The recovery of vascular tone in choroidal vessels seems to be different from the cardiovascular response. Our findings indicate that reduced fundus pulsations after L-NMMA are caused by systemic factors as well as by local reactions of the choroidal vasculature.

Effect of nitric oxide synthase inhibition on renal hemodynamics in humans: reversal by L-arginine.

Animal experiments indicate that inhibition of nitric oxide synthase (NOS) influences renal hemodynamics and that this effect can be reversed by L-arginine, the precursor of NO synthesis. We have therefore studied the effects of an inhibitor of NOS, N(G)-monomethyl-L-arginine (L-NMMA), and a subsequent coinfusion with L-arginine on renal hemodynamics. In a double-blind, randomized crossover design, eight healthy volunteers (means +/- 1SD, 25.6 +/- 3.1 yr) received a primed constant infusion of L-NMMA (3 mg/kg bolus infusion over 5 min, followed by 50 microg x kg(-1) x min(-1) over 120 min) with subsequent coinfusion of L-arginine (17 mg x kg(-1) x min(-1) over 30 min). In the absence of a hypertensive response, L-NMMA decreased renal plasma flow to 79% of baseline (P < 0.005); this effect was abrogated by L-arginine. Glomerular filtration rate was not affected, NO exhalation was reduced to 30% of baseline (P < 0.005) by L-NMMA, and this effect was attenuated by L-arginine. Our results demonstrate that basal NO production maintains renal blood flow in vivo in humans. In addition, the renal vasculature is particularly sensitive to inhibition of NOS, and these pharmacodynamic effects can be reversed by excess doses of L-arginine.

Effects of angiotensin-II infusion at pressor and subpressor doses on endothelin-1 plasma levels in healthy men.

Several lines of evidence suggest that effects of angiotensin-II (A-II) could be mediated in part by endothelin-1 (ET-1): A-II enhances production and secretion of ET-1 which in turn may contribute to the pressor effects and mitogenic actions of A-II. We have conducted a randomized controlled cross-over study to investigate whether A-II increases ET-1 plasma levels in humans at pressor doses. Each of the eight healthy male volunteers received a subpressor and pressor dose of A-II which were assessed by titration of the individual dose dependent blood pressure responses to A-II-infusion. The mean subpressor dose of A-II was 0.62 ng/kg/min. (range: 0.31-1.25); the mean pressor dose of A-II was 8.44 ng/kg/min. (range 2.5-20), yielding an average increase in mean arterial pressure by 35% (95% confidence interval [CI]: 24-45%). Plasma ET-1 concentrations increased significantly only in response to pressor doses of A-II (Friedman ANOVA p=0.022): ET-1 increased by 89 % (CI: 24-154%) over baseline (1.7 pmol/L; CI: 1.4-2.0) 60 min. after starting the pressor infusion of A-II and remained elevated throughout the 4-hours observation period. In conclusion, A-II at pressor doses but not at subpressor doses induced an increase in plasma levels of ET- 1 in healthy subjects. This finding may be of relevance for various diseases associated with increased production of A-II and could potentially have therapeutic implications.

Cerebral and ocular hemodynamic effects of sumatriptan in the nitroglycerin headache model.

BACKGROUND AND PURPOSE: Sumatriptan is a selective 5-hydroxytryptamine1d (5-HT1d)-receptor agonist, highly effective in the short-term treatment of migraine headaches. However, the mechanism underlying the action of sumatriptan is not yet completely understood. To further characterize the vascular effects of sumatriptan, we studied the effects on cerebral and ocular circulation in the well-established nitroglycerin headache model. METHODS: In a double-blind, placebo-controlled, randomized, two-way crossover study in 10 healthy male subjects, we administered either placebo plus nitroglycerin or sumatriptan plus nitroglycerin. Blood flow velocity in the middle cerebral artery and the ophthalmic artery, as well as ocular fundus pulsations and systemic hemodynamic parameters, were measured after sumatriptan and placebo and during the following infusion of nitroglycerin. RESULTS: After infusion of nitroglycerin, blood flow velocity in the middle cerebral decreased by -13.3% versus baseline after placebo pretreatment, but by only -2.2% after sumatriptan (treatment effect, +10.8%; p < 0.05). In contrast, sumatriptan had no effect in the ophthalmic artery. Ocular fundus pulsations, which estimate local pulsatile ocular blood flow, were slightly reduced after sumatriptan. Moreover, sumatriptan partially prevented the increase in fundus pulsations during nitroglycerin infusion (treatment effect, -5.4%; p < 0.05). CONCLUSIONS: Sumatriptan prevents the effect of nitroglycerin-induced vasodilation in the middle cerebral artery but not in the ophthalmic artery, which strongly supports the concept that sumatriptan directly vasoconstricts distended basal cerebral arteries. Measurement of ocular fundus pulsations indicates that sumatriptan also has a small vasoconstrictor action on resistance vessels.

Effects of estradiol on circulating P-selectin.

The membrane protein P-selectin tethers leukocytes to endothelial cells (EC) and on activated platelets, and may play a role in atherosclerosis. Lower plasma levels of a soluble (c) P-selectin have recently been observed in premenopausal women compared to those in men. Given the antiatherogenic-cardioprotective effect of 17 beta-estradiol (E2), we hypothesized that E2 may down-regulate the expression of P-selectin and subsequently decrease cP-selectin levels. The effects of E2 on levels of plasma cP-selectin were evaluated during the menstrual cycle in healthy women (n = 18) and by measuring the effect of a single im injection of 10 mg E2 valerate (n = 9) or placebo (n = 10) on cP-selectin levels in healthy male volunteers. In women, the cyclic increase in serum E2 concentrations was accompanied by a decrease in cP-selectin levels from 110 ng/mL [95% confidence interval (CI), 100-137 ng/mL] in the follicular phase. The decrease reached a maximum of 13% (95% CI, 2-19%, P = 0.014) in the luteal phase. In men, cP-selectin decreased from a median of 139 ng/mL (95% CI, 113-165) to 125 ng/mL (95% CI, 97-152; P = 0.038) 4 days after E2 injection. The median baseline value of cP-selectin in the 19 male volunteers was 133 ng/mL (95% CI, 115-143 ng/mL) and was approximately 30% higher than those in the female volunteers during the midcycle (P = 0.024) and luteal (P = 0.012) phases, but was not different from that during the follicular phase. In sum, our study suggests that E2 lowers cP-selectin levels. An E2-induced decrease in cP-selectin reflects either decreased activation or damage of platelets and/or endothelial cells in vivo. Thus, our study may point to an additional mechanism for the residual antiatherogenic-cardioprotective effect of E2 that cannot be explained by its lipid-lowering effects.

Altered reactivity of the inferior vena cava to noradrenaline and acetylcholine following the blockade of EDRF-biosynthesis with NG-nitro-L-arginine methyl ester.

1. Endothelium-derived relaxing factor (EDRF) has been shown to influence arterial tone, but controversial results have been obtained studying veins. The present study was performed to determine the importance of EDRF for the inferior vena cava in the rabbit and whether blockade of the synthesis of EDRF with NG-nitro-L-arginine methyl ester may influence the reactivity of the inferior vena cava to noradrenaline. 2. The inferior vena cava was excised in six New Zealand white rabbits and 12 rings were prepared for organ bath studies. Concentration-response curves were constructed for acetylcholine (10(-9)-10(-4) mol/L) and noradrenaline (10(-9)-10(-4) mol/L) before and following the administration of NG-nitro-L-arginine methyl ester. 3. All rings showed concentration-dependent relaxation to acetylcholine (mean maximum: 57 +/- 9%) following precontraction with noradrenaline (EC50:10(-6) mol/L). Following NG-nitro-L-arginine methyl ester, this dilation was significantly reduced to a mean maximum relaxation of 13 +/- 6% (P < 0.01). 4. Contraction of the inferior vena cava to increasing doses of noradrenaline reached a maximum of 5.8 +/- 2.8 g before NG-nitro-L-arginine methyl ester (basal tension 1.0 +/- 0.5 g). NG-nitro-L-arginine methyl ester did not affect basal tension, but the constrictor response to noradrenaline was enhanced significantly to a maximum of 9.1 +/- 3.8 g (P < 0.01). 5. Although it cannot be ascertained definitively from the present results, it is suggested that EDRF is mediating vasodilation of the inferior vena cava and that this vasoactive agent may also contributes significantly to the modulation of the reactivity to catecholamines.

Expression of VCAM-1 in rabbit iliac arteries is associated with vasodilator dysfunction of regenerated endothelium following balloon injury.

Previous studies have demonstrated impaired endothelium-dependent vasodilation following balloon injury of the rabbit iliac artery, suggesting dysfunction of the regenerated endothelium. More recently, expression of vascular cell adhesion molecule-1 (VCAM-1) has been shown up to 4 weeks in a different injury model of the rabbit aorta, suggesting sustained inflammatory activation of endothelium following injury. The aim of the present study was to combine the examination of VCAM-1 expression, as a marker of cellular activation, and the assessment of endothelium-dependent relaxation to test the hypothesis that different forms of altered endothelial function are concurrently present in the chronic phase following experimental balloon angioplasty. New Zealand White rabbits fed either a standard (n = 7) or a 1% cholesterol (n = 8) diet, underwent balloon injury of the iliac artery 5 weeks following the initiation of the diet. Four weeks after balloon injury, control and balloon-injured arteries were harvested for in vitro studies of vascular reactivity, for morphometric analysis and for immunocytochemical staining with Rb 1/9 monoclonal antibody directed against VCAM-1 and with CD 31 monoclonal antibody for the identification of endothelial cells. The combination of balloon injury and hypercholesterolemia resulted in a marked impairment of endothelium-dependent relaxation to acetylcholine and in a pronounced intimal proliferation compared to control or either intervention alone. Control rings of rabbits fed a normal diet did not reveal positive staining for VCAM-1. Balloon-injured rings of the animals fed a normal diet showed focal areas of positive staining in the superficial cell layer overlying intimal lesions. In the group fed a high cholesterol diet, control rings and ballooned rings showed positive staining for VCAM-1 in cells overlying intimal lesions. In all groups the superficial cell layers were identified as endothelial cells by positive staining for CD 31. In conclusion, the present study shows that regenerated endothelium following mechanical arterial injury reveals expression of VCAM-1 together with impaired receptor-mediated vasodilator capacity. Thus, the expression of VCAM-1 and the impairment of endothelium-dependent relaxation may represent different features of endothelial dysfunction following balloon injury which may actively influence the proliferative lesion of restenosis after balloon angioplasty.

Sex differences in concentrations of exhaled nitric oxide and plasma nitrate.

Nitric oxide (NO) is generally considered as an endogenous vasoprotective agent. Various studies indicate that the female sex hormone estradiol, that contributes to the well known gender differences in cardiovascular disease, may enhance NO-production. Thus we studied sex differences in NO-generation by measuring single breath NO-exhalation and plasma levels of nitrate (NO3), the stable endmetabolite of NO. In this observational trial 22 male and 21 female volunteers, 19 to 38 years of age, were studied on 3 days at weekly intervals. Median concentrations of NO were 20 parts per billion (95% CI: 16 to 32 ppb) in women and 34 ppb (95% CI: 31 to 58 ppb) in men. The median plasma concentrations of NO3 were 14 microM/L (95% CI: 11 to 23 microM/L) in women and 27 microM/L (95% CI: 24 to 47 microM/L) in men. Thus, men exhaled 59% more NO (p < 0.001) and had 99% higher NO3 levels than women (p < 0.0001). Even when exhaled NO concentrations were corrected for body weight, men exhaled 50% more NO than women (p = 0.024). No significant changes in measured endpoints were seen during the menstrual cycle (p > 0.05) in women. In view of the diversity of NO-actions, the finding of marked sex differences in NO-production is basic to the elucidation of gender differences in a number of (patho)-physiologic conditions.

Influence of angiotensin II on circulating adhesion molecules and blood leukocyte count in vivo.

The mechanism of the beneficial effect of angiotensin converting enzyme inhibitors in patients with myocardial infarction is not clear. Recent in vitro data indicate that angiotensin II (AII) stimulates the expression of adhesion molecules and thus activates leukocyte endothelial interactions. In eight healthy volunteers we investigated the influence of exogenous AII on circulating adhesion molecules and on the blood leukocyte count. A systemically effective and a systemically ineffective dose of AII were administered intravenously over 4 h in a single blind crossover design. Examination of the time course of circulating intercellular and vascular adhesion molecules and E-selectin (cICAM-1, cVCAM-1, cE-selectin-1) in response to the AII infusion revealed increases of up to 11% (especially in cVCAM-1 levels) at single time points, but no significant sustained elevation or trend that can be interpreted as a drug-induced effect. The systemically effective dose, which induced an increase in mean arterial blood pressure from 80 to 108 mmHg (1 mmHg = 133.3 Pa), resulted in a significant increase in blood leukocytes, from 4.8 +/- 0.3 to 5.5 +/- 0.3 g/L (p < 0.05); the systemically ineffective AII dose did not alter blood leukocyte count significantly. Although we did not find an influence of AII on circulating adhesion molecules in vivo, we observed an increase in the blood leukocyte count; thus it may be intriguing to assess whether renin-angiotensin system modulating drugs might exert their favorable effect in ischemic diseases at least in part via an influence on leukocytes.

Short-term drug effects on the signal-averaged electrocardiogram in healthy men: assessment of intra- and interindividual variability of spectral temporal mapping and time-domain analysis.

The effect of cardiovascular drugs on the results of the signal-averaged electrocardiogram (SA-ECG) was studied in healthy young subjects. Cardiovascular drugs may confound the analysis of SA-ECG, but the effect of drugs on time-domain analysis and on spectral temporal mapping (STM) in healthy subjects has not been investigated under standardized conditions. Also, the reproducibility of the various spectral area measurements of STM has not been assessed simultaneously. Short-term drug effects on the SA-ECG were studied in 20 healthy young men (age 23.5 +/- 2.5 years) in an observer-blinded, crossover design on separate days. Each subject was randomly assigned to four drugs. The SA-ECG was recorded at baseline and during i.v. administration of stepwise increased doses of adenosine, atropine, isoproterenol, lidocaine, norepinephrine, propranolol, verapamil and placebo. Low amplitude signal duration was significantly and dose-dependently shortened by isoproterenol, whereas no consistent effect on the filtered QRS duration or on the root mean square voltage in the terminal 40 ms of time-domain analysis was noted for any of the other drugs. Only lidocaine significantly and dose-dependently decreased the parameters of STM at QRS offset and +20 ms, even though short-term reproducibility and day-to-day reproducibility of spectral area measurements were low. Interpretation of "normal" results from SA-ECG is not relevantly influenced by the studied drugs at clinical doses. STM may prove a useful technique for detection of the actions of sodium channel-blocking drugs. Reproducibility of STM measurements is substantially lower than that of time-domain parameters.

Role of nitric oxide in hemostatic system activation in vivo in humans.

NO is a potent inhibitor of in vitro platelet aggregation and adhesion. In view of possible future widespread use of NO in pulmonary and cardiovascular diseases, we investigated the role of NO in hemostatic system activation in vivo in humans. Sixteen healthy male volunteers (age range, 22 to 33 years) received either NO by inhalation (50 ppm over 30 minutes; n = 8) or the NO synthase inhibitor NG-monomethyl L-arginine (L-NMMA 3mg/kg body weight i.v. over 5 minutes; n = 8), beta-Thromboglobulin (beta-TG), an indicator of platelet activity; prothrombin fragment 1 + 2 (F 1 + 2), an index of coagulation activation; and thromboxane B2 (TxB2), a measure of platelet prostaglandin synthesis, were determined in blood samples obtained from bleeding-time incisions ("shed blood") at baseline and after administration of the respective drug. In addition, beta-TG and F 1 + 2 were also determined in venous blood. To verify the systemic effects of the drugs, methemoglobin and plasma nitrites/nitrates were measured in the NO group, and cardiac output and exhaled NO were measured in the L-NMMA group. Compared with baseline, methemoglobin and plasma nitrates increased by 73 +/- 12% (P= .006) and 60 +/- 9% (P< .001), respectively, following NO inhalation. L-NMMA infusion resulted in decreases in both cardiac output by 16 +/- 2%; P< .001) and exhaled NO (by 54 +/- 7%; P< .001). NO inhalation or L-NMMA infusion had no significant effect on beta-TG, F 1 + 2, and TxB2 levels in shed blood.(ABSTRACT TRUNCATED AT 250 WORDS)