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A number of studies have reported on the successful use of intravenous glycoprotein IIb/IIIa receptor antagonists in patients with unstable angina or undergoing percutaneous interventions. The promise of interrupting the aggregation of platelets in the setting of unstable plaques on a chronic basis had led to the evaluation of several oral agents for longer-term administration. The development program of two of these agents, xemilofiban and orbofiban, will be reviewed and evaluated to understand the selection process of therapeutic targets for use based upon complex pharmacokinetic and pharmacodynamic responses. A review of the pivotal phase III trial results will also be provided along with insights into the potential reasons for the lack of significant benefit shown with these agents to date.

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Arousal from sleep is associated with elevated cardiac and respiratory activity. It is unclear whether this occurs because of homeostatic mechanisms or a reflex activation response associated with arousal. Cardiorespiratory activity was measured during spontaneous arousals from sleep in subjects breathing passively on a ventilator. Under such conditions, homeostatic mechanisms are eliminated. Ventilation, end-tidal PCO2, mask pressure, diaphragmatic electromyograph, heart rate, and blood pressure were measured in four normal subjects under two conditions: assisted ventilation and a normal ventilation control condition. In the control condition, there was a normal, sleep-related fall in ventilation and rise in end-tidal PCO2. Subsequently, at an arousal, there was an increase in respiratory and cardiac activity. In the ventilator condition, a vigorous cardiorespiratory response to a spontaneous arousal from sleep remained. These results indicate that sleep-related respiratory stimuli are not necessary for the occurrence of elevated cardiorespiratory activity at an arousal from sleep and are consistent with the hypothesis that such activity is at least in part due to a reflex activation response.

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While there is a developing understanding of the influence of sleep on cardiovascular autonomic activity in humans, there remain unresolved issues. In particular, the effect of time within the sleep period, independent of sleep stage, has not been investigated. Further, the influence of sleep on central sympathetic nervous system (SNS) activity is uncertain because results using the major method applicable to humans, the low frequency (LF) component of heart rate variability (HRV), have been contradictory, and because the method itself is open to criticism. Sleep and cardiac activity were measured in 14 young healthy subjects on three nights. Data was analysed in 2-min epochs. All epochs meeting specified criteria were identified, beginning 2 h before, until 7 h after, sleep onset. Epoch values were allocated to 30-min bins and during sleep were also classified into stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. The measures of cardiac activity were heart rate (HR), blood pressure (BP), high frequency (HF) and LF components of HRV and pre-ejection period (PEP). During non-rapid eye movement (NREM) sleep autonomic balance shifted from sympathetic to parasympathetic dominance, although this appeared to be more because of a shift in parasympathetic nervous system (PNS) activity. Autonomic balance during REM was in general similar to wakefulness. For BP and the HF and LF components the change occurred abruptly at sleep onset and was then constant over time within each stage of sleep, indicating that any change in autonomic balance over the sleep period is a consequence of the changing distribution of sleep stages. Two variables, HR and PEP, did show time effects reflecting a circadian influence over HR and perhaps time asleep affecting PEP. While both the LF component and PEP showed changes consistent with reduced sympathetic tone during sleep, their pattern of change over time differed.

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Arousals from sleep can be associated with increases in blood pressure (BP). However, it is uncertain whether this is due to a direct effect of arousals on BP, or is secondary to respiratory stimuli present at the time of the arousal. Cheyne-Stokes respiration (CSR) in patients with congestive heart failure (CHF) provides unique conditions that may allow these two possibilities to be distinguished. In CSR, the apnea-hyperpnea cycle can be dissociated from arousals because when CSR occurs during wakefulness, it does so in the absence of arousals, and when it occurs during sleep, arousals occur either at the termination of apnea (early arousals) or several breaths after the onset of hyperpnea (late arousals). We therefore measured BP during wakefulness and non-rapid eye movement (NREM) sleep in eight patients with CHF and CSR. During wakefulness, CSR was associated with wide fluctuations in systolic BP (mean +/- SD, 11.3 +/- 6.0 mm Hg) synchronous with the apnea-hyperpnea cycle, in the absence of arousals. Similar fluctuations in BP were observed during CSR with early arousals (13. 7 +/- 7.0 mm Hg) in NREM sleep. However, late arousals during CSR were associated with a small, but significant additional effect on systolic BP (14.2 +/- 7.1 mm Hg, p < 0.05). Furthermore, the degree of BP increase following arousals was directly related to the associated increase in ventilation (r = 0.70, p < 0.05). We conclude that BP fluctuations during CSR in patients with CHF are primarily related to oscillations in ventilation during the CSR cycle and can occur in the absence of arousals. Arousals augment these BP oscillations, but only when they occur late in hyperpnea.

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BACKGROUND: When administered intravenously at the time of percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor antagonists decrease the incidence of death and nonfatal myocardial infarction and the need for urgent revascularization. We hypothesized that long-term administration of oral glycoprotein IIb/IIIa antagonists, which block the aggregation of platelets, might stabilize intravascular plaque and prevent additional ischemic cardiac events. METHODS: We conducted a prospective, double-blind trial in which 7232 patients were randomly assigned to receive 20 mg of oral xemilofiban or placebo 30 to 90 minutes before undergoing percutaneous coronary revascularization, with maintenance doses of 10 or 20 mg of xemilofiban or placebo administered three times daily for up to 182 days. There were two primary composite end points: one was death, nonfatal myocardial infarction, or urgent revascularization at 182 days, and the other was death or nonfatal myocardial infarction at 182 days. RESULTS: Death, myocardial infarction, or urgent revascularization occurred within 182 days in 324 patients who received placebo (Kaplan-Meier cumulative event rate, 13.5 percent), 332 who received 10 mg of xemilofiban (13.9 percent, P=0.82 for the comparison with placebo), and 306 who received 20 mg of xemilofiban (12.7 percent, P=0.36 for the comparison with placebo). The incidence of death or myocardial infarction was also similar in all three groups. Clinically significant hemorrhagic complications and thrombocytopenia were infrequent. CONCLUSIONS: The administration of the glycoprotein IIb/IIIa antagonist xemilofiban before percutaneous coronary revascularization and for up to six months thereafter does not significantly reduce the incidence of important clinical end points.

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Previous work has shown that the magnitude of state-related ventilatory fluctuations is amplified over the sleep-onset period and that this amplification is partly due to peripheral chemoreceptor activity, because it is reduced by hyperoxia (J. Dunai, M. Wilkinson, and J. Trinder. J. Appl. Physiol. 81: 2235-2243, 1996). These data also indicated considerable intersubject variability in the magnitude of amplification. A possible source of this variability is individual differences in peripheral chemoreceptor drive (PCD). We tested this hypothesis by measuring state-related ventilatory fluctuations throughout sleep onset under normoxic and hyperoxic conditions in subjects with high and low PCD. Results demonstrated that high-PCD subjects experienced significantly greater amplification of state-related ventilatory fluctuations than did low-PCD subjects. In addition, hyperoxia significantly reduced the amplification effect in high-PCD subjects but had little effect in low-PCD subjects. These results indicate that individuals with high PCD are likely to experience greater sleep-related ventilatory instability and suggest that peripheral chemoreceptor activity can contribute to sleep-disordered breathing.

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Alterations in a number of measures of cardiac activity were examined during sleep onset in 6 participants over 3 experimental nights. Each sleep onset was divided into four consecutive phases: wakefulness, mixed alpha and theta activity, stage 2 NREM sleep with arousals, and stable stage 2 sleep. The variables measured were heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP) and T-wave amplitude (TWA). Respiration rate (RR) was also measured. HR and RR were lower in stable Stage 2 sleep compared with wakefulness, whereas PEP, TWA and RSA did not change significantly. During the second and third phases of sleep onset, HR decreased at each transition into sleep and increased following each spontaneous arousal. This increase resolved rapidly, with a return to sleep levels by 12 beats after the arousal. HR changes are discussed with reference to RSA, PEP, TWA and the concept of a waking reflex.

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Ventilation decreases and airway resistance increases with the loss of electroencephalogram alpha activity at sleep onset. The aim of this study was to determine whether reflexive load compensation is lost immediately on the loss of alpha activity. Six healthy male subjects were studied under two conditions (load and control-no load), in three states (continuous alpha, continuous theta, and immediately after a transition from alpha to theta), and in two phases (early and late sleep onset). Ventilation and respiratory timing were measured. A comparison of loaded with control conditions indicated that loading had no effect on inspiratory minute ventilation during continuous alpha (differential effect of 0.00 l/min) and only a small, nonsignificant effect in theta immediately after phase 2 transitions (0.31 l/min), indicating a preservation of load compensation at these times. However, there were significant decreases in inspiratory minute ventilation on loaded trials during continuous theta in phase 2 (0.77 l/min) and phase 3 (1.15 l/min) and during theta immediately after a transition in phase 3 (0.87 l/min), indicating a lack of reflexive load compensation. The results indicate that, because reflex load compensation is state dependent, state-related changes in airway resistance contribute to state-related changes in ventilation during sleep onset. However, this effect was slightly delayed with transitions into theta early in sleep.

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At the onset of non-rapid-eye-movement (NREM) sleep there is a fall in ventilation and an increase in upper airway resistance (UAR). In healthy men there is a progressive increase in UAR as NREM sleep deepens. This study compared the pattern of change in UAR and ventilation in 14 men and 14 women (aged 18-25 yr) both during sleep onset and over the NREM phase of a sleep cycle (from wakefulness to slow-wave sleep). During sleep onset, fluctuations between electroencephalographic alpha and theta activity were associated with mean alterations in inspiratory minute ventilation and UAR of between 1 and 4.5 l/min and between 0.70 and 5.0 cmH2O . l-1 . s, respectively, with no significant effect of gender on either change (P > 0.05). During NREM sleep, however, the increment in UAR was larger in men than in women (P < 0.01), such that the mean levels of UAR at peak flow reached during slow-wave sleep were approximately 25 and 10 cmH2O . l-1 . s in men and women, respectively. We speculate that the greater increase in UAR in healthy young men may represent a gender-related susceptibility to sleep-disordered breathing that, in conjunction with other predisposing factors, may contribute to the development of obstructive sleep apnea.

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In studies of elderly individuals, ventilation and EEG-defined arousal have been shown to vary periodically and synchronously. Such results have been interpreted as indicating the primacy of sleep/wake state in causing ventilatory instability during sleep onset. However, because the elderly individuals studied were periodic breathers, the results do not unequivocally support this conclusion. In this study the relationship between ventilation and EEG-defined arousal was assessed in a group of 21 young, healthy men in whom ventilatory instability during sleep onset was not periodic. Ventilation and EEG (O1-A2) recordings were collected, and the longest uncontaminated periods from early and late in sleep onset were selected for subsequent analysis. The 84 time series (21 subjects, 2 variables, and 2 occasions in sleep onset) were subjected to spectral analysis to identify periodicity, and the relationship between the two variables was determined by cross-correlational methods. The results indicated that the time series were nonperiodic, yet significant correlations were observed between the two variables. The data support the view that during sleep onset ventilatory instability is driven primarily by variations in sleep/wake arousal level.

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An 86-year-old patient with a history of chronic angina pectoris and a remote cerebrovascular accident presented to the hospital with an acute myocardial infarction complicated by a concomitant nonhemorrhagic cerebrovascular accident. Postmyocardial infarction angina pectoris, refractory to maximal medical therapy, led to coronary angiography. This demonstrated the "culprit" lesion to be a complex and critical atherosclerotic lesion at the distal-most extent of a long area of left anterior descending (LAD) myocardial bridging. This "culprit" lesion was successfully treated by balloon angioplasty. This is the second report in the recent literature of balloon angioplasty revascularization used in this fashion. Similarities and differences between our case report and the prior report in the literature are compared and contrasted.

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An 81-year-old woman who was 4 years post 3-vessel coronary artery bypass graft (CABG) surgery suffered a non-Q-wave myocardial infarction. Angiography revealed the recent occlusion of a saphenous vein graft (SVG) to an obtuse marginal coronary artery. Five days following failure of intragraft urokinase and systemic heparinization to recanalize the SVG, balloon angioplasty was undertaken. A mobile thrombus was observed to migrate spontaneously in a retrograde manner in the SVG and was removed during PTCA by aspiration through the guiding catheter.

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Light accelerates degeneration of photoreceptor cells of the retinal degeneration B (rdgB) mutant of Drosophila. During early stages of degeneration, light stimuli evoke spikes from photoreceptors of the mutant fly; no spikes can be recorded from photoreceptors of the wild-type fly. Production of spike potentials from mutant photoreceptors was blocked by diltiazem, verapamil hydrochloride, and cadmium. Little, if any, effect of the (-)-cis isomer or (+)-cis isomer of diltiazem on the light response was seen. Further, the (+)-cis isomer was approximately 50 times more effective than the (-)-cis isomer in blocking the Ca2+ spikes, indicating that diltiazem action on the rdgB eye is mediated by means of blocking voltage-sensitive Ca2+ channels, rather than by blocking the light-sensitive channels. Application of the Ca(2+)-channel blockers (+)-cis-diltiazem and verapamil hydrochloride to the eyes of rdgB flies over a 7-day period largely inhibited light-dependent degeneration of the photoreceptor cells. Pulse labeling with [32P]phosphate showed much greater incorporation into eye proteins of [32P]phosphate in rdgB flies than in wild-type flies. Retarding the light-induced photoreceptor degeneration in the mutant by Ca(2+)-channel blockers, thus, suggests that toxic increase in intracellular Ca2+ by means of voltage-gated Ca2+ channels, possibly secondary to excessive phosphorylation, leads to photoreceptor degeneration in the rdgB mutant.

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To study the effects of digoxin on regional left ventricular performance, continuous ventricular dynamics were assessed in nine patients with stable coronary disease. Computer-assisted analysis of the fluoroscopic motion of surgically implanted mid wall myocardial markers was used. The markers define six minor ventricular radii and outline the left ventricle. One and one-half hours after administration of 1 mg of intravenous digoxin, mean velocity of circumferential fiber shortening for all segments increased 19 percent, from 0.67 +/- 0.06 to 0.78 +/- 0.06 circumference/sec (P less than 0.01) and ejection fraction increased 4.5 percent, from 0.50 +/- 0.03 to 0.53 +/- 0.03 (P less than 0.05). Segmental velocity of circumferential fiber shortening, total segmental shortening and early segmental systolic shrtening increased in 83 percent to 91 percent of normal segments, depending on which index was used. Only 45 to 55 percent of initially abnormal segments benefited from digoxin. In general, segmental dyssynergy increased even when net ventricular function was enhanced. These results suggest that in pateints with chronic left ventricular contraction abnormalities due to coronary disease, deterioration of performance in abnormal regions after administration of digoxin may result from increased stress imposed by increased afterload and by improved segmental dynamics in more normal areas.

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To assess the circulatory effects of afterload reduction and inotropism individually and in combination as rational therapy for refractory heart failure, nitroprusside and dopamine were administered to 13 patients with severe cardiac decompensation. Dopamine at average doses of 3 and 7 microgram/kg per min produced increases in cardiac output and reductions in peripheral resistance. At doses of 15 microgram/kg per min, dopamine increased heart rate, peripheral arterial pressure and side effects. Nitroprusside alone decreased left-sided filling pressures and increased cardiac output. When the agents were administered together, the increases in cardiac output were significantly greater than with either agent alone and there was physiologic improvement in overall circulatory function. The relations among changes in afterload (systemic impedence), preload (filling pressures) and cardiac index help to explain the salutary effects of combined therapy in patients with refractory heart failure.

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