Comparison of coronary stent expansion by intravascular ultrasonic imaging in younger versus older patients with diabetes mellitus.

The poor long-term outcome in young diabetic patients receiving stents is not well understood. The purpose of this study was to characterize the pastprocedural results of stent placement in diabetic patients using intravascular ultrasound to identify factors that might be associated with poor clinical outcome. The acute dimensions from intravascular ultrasound studies after stent deployment at 5 sites were measured from 39 coronary segments from patients with diabetes mellitus (DM) and 161 segments from nondiabetic patients (non-DM). Within these 2 groups, segments were subgrouped into young (y) and old (o) in reference to the mean study age of 64 years, forming 4 groups: yDM (n = 20), y non-DM (n = 65), oDM (n = 19), and o non-DM (n = 96). Results are reported as mean +/- 1 SD. Diabetic patients had smaller mean lumen area within the treated segment than o non-DM (8.37+/-2.59 vs. 9.11+/-3.35 mm2, p<0.01). These differences were more pronounced at the distal reference vessel lumen of yDM than y non-DM (7.6+/-2.3 vs. 10.3+/-4.5 mm2, p<0.003), and were associated with greater percent plaque area in the distal reference vessel (43.4+/-13% vs. 34.1+/-11.2%, p<0.003). In young diabetic patients undergoing elective stent placement, underexpansion of the stented segment is common, which may contribute to the relatively poor long-term outcome in these patients. We suggest that when stenting is the procedure of choice in this subgroup of high-risk patients, special attention should be given to optimizing lumen dimensions.

Three-year clinical and angiographic follow-up after intracoronary radiation : results of a randomized clinical trial.

BACKGROUND: Although several early trials indicate treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The objective of this report is to document angiographic and clinical outcome 3 years after treatment of restenotic stented coronary arteries with catheter-based (192)Ir. METHODS AND RESULTS: A double-blind, randomized trial compared (192)Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Over a 9-month period, 55 patients were enrolled; 26 were randomized to (192)Ir and 29 to placebo. At 3-year follow-up, target-lesion revascularization was significantly lower in the (192)Ir group (15. 4% versus 48.3%; P<0.01). The dichotomous restenosis rate at 3-year follow-up was also significantly lower in (192)Ir patients (33% versus 64%; P<0.05). In a subgroup of patients with 3-year angiographic follow-up not subjected to target-lesion revascularization by the 6-month angiogram, the mean minimal luminal diameter between 6 months and 3 years decreased from 2.49+/-0.81 to 2.12+/-0.73 mm in (192)Ir patients but was unchanged in placebo patients. CONCLUSIONS: The early clinical benefits observed after treatment of coronary restenosis with (192)Ir appear durable at late follow-up. Angiographic restenosis continues to be significantly reduced in (192)Ir-treated patients, but a small amount of late loss was observed between the 6-month and 3-year follow-up time points. No events occurred in the (192)Ir group to suggest major untoward effects of vascular radiotherapy. At 3-year follow-up, vascular radiotherapy continues to be a promising new treatment for restenosis.

Effect of intracoronary gamma-radiation therapy on in-stent restenosis: An intravascular ultrasound analysis from the gamma-1 study.

BACKGROUND: The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of gamma-radiation on recurrent in-stent restenosis. METHODS AND RESULTS: After successful reintervention, patients were randomized to receive either (192)Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the (192)Ir patients than the placebo patients (-25+/-34 mm(3) versus -48+/-42 mm(3); P:=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the (192)Ir patients than in the placebo patients (28+/-37 mm(3) versus 50+/-40 mm(3); P:=0.0352). When averaged over the length of the stented segment (32+/-13 mm versus 33+/-14 mm; P:=0.9), the increase in mean area of intimal hyperplasia was 0.8+/-1.0 mm(2) in the (192)Ir group and 1.6+/-1.2 mm(2) in the control group (P:=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no (192)Ir patients. CONCLUSIONS: gamma-Radiation therapy can effectively prevent recurrent in-stent restenosis by inhibiting neointimal formation within the stent. At the stent edge, there were no significant differences between (192)Ir and placebo patients.

Axial movement of the intravascular ultrasound probe during the cardiac cycle: implications for three-dimensional reconstruction and measurements of coronary dimensions.

BACKGROUND: Motion of the intravascular ultrasound (IVUS) probe within the coronary artery from cardiac contraction may result in artifacts during 3-dimensional ultrasound image reconstruction and inaccurate measurements of coronary compliance. The purpose of this study was to establish whether longitudinal movement of the IVUS transducer in the coronary artery occurs and to quantify such motion. METHODS: In 31 patients we positioned IVUS transducers at 59 coronary branch points: 41 in the left anterior descending coronary artery, 11 in the left circumflex coronary artery, and 7 in the right coronary artery. In each image sequence the branching vessel oscillated in and out of the imaging plane during the cardiac cycle, confirming longitudinal transducer movement. The extent of movement was estimated by IVUS from the dimension of the branch vessel traversed. In addition, angiographic visualization and measurement of IVUS probe motion was performed at 17 branch points in 12 patients. RESULTS: Average longitudinal transducer movement as measured by IVUS was 1.50 +/- 0.80 mm (n = 46, range 0.5 to 5.5 mm). Because IVUS could not account for probe motion that exceeded the vessel branch diameter, the values obtained represent minimum movement. Average probe motion as assessed by cineangiography in a subset of 12 patients was 2.43 +/- 1.42 mm (range 0.57 to 6.56 mm). CONCLUSIONS: This study establishes that longitudinal movement of IVUS transducers within coronary vessels occurs during the cardiac cycle. Because documented extent of motion may be sufficient to influence analysis, IVUS images are best obtained with electrocardiographic gating.

Quantitative angiographic analysis of stent restenosis in the Scripps Coronary Radiation to Inhibit Intimal Proliferation Post Stenting (SCRIPPS) Trial.

To identify luminal dimension changes occurring within the stent alone and within the stent + margin segment, we reviewed the quantitative angiographic results obtained from the Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial, a prospective randomized trial assessing the effect of iridium-192 (Ir-192) on the prevention of stent restenosis. Fifty-five patients were randomly assigned to receive Ir-192 or placebo sources after successful intervention. Procedural and 6-month follow-up cineangiograms were quantitatively reviewed in 52 patients to identify changes within the stent and the stent + margin segment. The percent diameter stenosis was lower within the stent than within the stent + margin segment after the procedure (6 +/- 22% vs 21+/- 15%, p <0.0001) and at follow-up (28 +/- 29% vs 42 +/- 21%, p <0.0001). As a result, a lower restenosis rate was found within the stent than within the stent + margin (25% vs 37%, p <0.0001); isolated stent margin restenosis occurred in 11.5% of lesions. Treatment with Ir-192 reduced restenosis within the stent (8% vs 39%; p = 0.010) and within the stent + margin segment (17% vs 54%; p = 0.010); the reduction in restenosis at the margin only (8.3% vs 14.3%, p = 0.503) was not significant. The lowest relative risk for restenosis resulting from Ir-192 occurred within the stent (0.21; 95% confidence interval [CI] 0.05 to 0.86) compared with the stent + margin segment (0.31; 95% CI 0.12 to 0.81) or the stent margin (0.58; 95% CI 0.12 to 2.91). In the SCRIPPS trial, 32% of restenosis occurred at the stent margins. Treatment with Ir-192 reduced restenosis primarily within the stent rather than the margin. Whether extending the treatment length to fully include the stent margins will further reduce restenosis requires further study.

Two-year follow-up after catheter-based radiotherapy to inhibit coronary restenosis.

BACKGROUND: Although early trials indicate the treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The possibility of late untoward consequences, such as aneurysm formation, perforation, and accelerated vascular disease, is of significant concern. Furthermore, it is not known whether the beneficial effects of radiation therapy will be durable or whether radiation will only delay restenosis. METHODS AND RESULTS: A double-blind, randomized trial was undertaken to compare 192Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Patients were randomly assigned to receive a 0.76-mm (0. 03-in) ribbon containing sealed sources of either 192Ir or placebo. All patients underwent repeat coronary angiography at 6 months. All living patients were contacted 24 months after their index study procedure. Patients were assessed with respect to the need for target-lesion revascularization or nontarget-lesion revascularization, occurrence of myocardial infarction, or death. Over a 9-month period, 55 patients were enrolled; 26 were randomized to 192Ir and 29 to placebo. Follow-up was obtained in 100% of living patients at a minimum of 24 months. Target-lesion revascularization was significantly lower in the 192Ir group (15.4% versus 44.8%; P<0. 01). Nontarget-lesion revascularization was similar in 192Ir and placebo patients (19.2% versus 20.7%; P=NS). There were 2 deaths in each group. The composite end point of death, myocardial infarction, or target-lesion revascularization was significantly lower in 192Ir-treated versus placebo-treated patients (23.1% versus 51.7%; P=0.03). No patient in the 192Ir group sustained a target-lesion revascularization later than 10 months. CONCLUSIONS: At 2-year clinical follow-up, treatment with 192Ir demonstrates significant clinical benefit. Although further follow-up (including late angiography) will be necessary, no clinical events have occurred to date in the 192Ir group to suggest major untoward effects of vascular radiotherapy. At the intermediate follow-up time point, vascular radiotherapy continues to be a promising new treatment for restenosis.

A subgroup analysis of the Scripps Coronary Radiation to Inhibit Proliferation Poststenting Trial.

INTRODUCTION: In the Scripps Coronary Radiation to Inhibit Proliferation Poststenting (SCRIPPS) Trial, 192Ir significantly reduced angiographic, ultrasonographic, and clinical endpoints of restenosis. The objective of this analysis was to quantitate the impact of patient, lesion and technical characteristics on late angiographic outcome. METHODS: Patients with restenotic, stented coronary lesions were randomized to receive either 192Ir or placebo sources. Late luminal loss and loss index were calculated for several patient subgroups, including patients with diabetes, in-stent restenosis, multiple previous percutaneous transluminal coronary angioplasty (PTCA) procedures, longer lesion lengths, saphenous vein grafts, small vessel diameters, and minimum dose exposures < 8.00 Gy. Two-factor analysis of variance was used to test for an interaction between patient characteristics and treatment effect. RESULTS: In the treated group, late loss was particularly low in patients with diabetes (0.19 mm), in-stent restenosis (0.17 mm), reference vessel diameters < 3.0 mm (0.07 mm), and patients who received a minimum radiation dose to the entire adventitial border of at least 8.00 Gy. The loss index in each of these subgroups was similarly low at -0.02, 0.03, -0.02, and 0.03, respectively. By 2-factor analysis of variance, a significant interaction between subgroup characteristic and treatment effect (late loss) was found in patients with in-stent restenosis (p = 0.035), and patients receiving a minimum dose of 8.00 Gy to the adventitial border (p = 0.009). CONCLUSION: In this pilot study, patient characteristics associated with a more aggressive proliferative response to injury appeared to confer an enhanced response to radiotherapy. Furthermore, a dose threshold response to 192Ir was found with an enhanced response occurring when the entire circumference of the adventitial border was exposed to at least 8.00 Gy.

Catheter-based radiotherapy to inhibit restenosis after coronary stenting.

BACKGROUND: In animal models of coronary restenosis, intracoronary radiotherapy has been shown to reduce the intimal hyperplasia that is a part of restenosis. We studied the safety and efficacy of catheter-based intracoronary gamma radiation plus stenting to reduce coronary restenosis in patients with previous restenosis. METHODS: Patients with restenosis underwent coronary stenting, as required, and balloon dilation and were then randomly assigned to receive catheter-based irradiation with iridium-192 or placebo. Clinical follow-up was performed, with quantitative coronary angiographic and intravascular ultrasonographic measurements at six months. RESULTS: Fifty-five patients were enrolled; 26 were assigned to the iridium-192 group and 29 to the placebo group. Angiographic studies were performed in 53 patients (96 percent) at a mean (+/-SD) of 6.7+/-2.2 months. The mean minimal luminal diameter at follow-up was larger in the iridium-192 group than in the placebo group (2.43+/-0.78 mm vs. 1.85+/-0.89 mm, P=0.02). Late luminal loss was significantly lower in the iridium-192 group than in the placebo group (0.38+/-1.06 mm vs. 1.03+/-0.97 mm, P=0.03). Angiographically identified restenosis (stenosis of 50 percent or more of the luminal diameter at follow-up) occurred in 17 percent of the patients in the iridium-192 group, as compared with 54 percent of those in the placebo group (P= 0.01). There were no apparent complications of the treatment. CONCLUSIONS: In this preliminary, short-term study of patients with previous coronary restenosis, coronary stenting followed by catheter-based intracoronary radiotherapy substantially reduced the rate of subsequent restenosis.

Ultrasound-guided stent placement.

IVUS imaging has dramatically increased understanding of the process of coronary stent placement. Preintervention or diagnostic IVUS has been shown to be of value before stent placement to assess lesion severity and length as well as the degree and location of calcification. Before stent placement, ultrasound dimensions may also be used to select the appropriate type and size of device. Although studies are in progress to define the role of prestent ultrasound imaging, much interest centers around the use of IVUS to detect significant superficial coronary calcium and direct rotational atherectomy before stent placement. Clinical trials have demonstrated the feasibility and safety of IVUS-guided coronary stent placement without postprocedure warfarin anticoagulation. Although it has been established subsequently that reduced anticoagulation may be administered to low-risk patients without IVUS guidance, three important points have been established by these trials. First, IVUS is superior to angiography for assessment of adequate stent expansion and apposition. As noted in several studies, angiography frequently overestimates lumen dimensions after stent placement. Second, IVUS-guided stent implantation yields larger acute stent dimensions. Third, IVUS-guided therapy in the form of additional stent placement or use of a larger balloon does not increase stent procedure complication rates when appropriate criteria for optimal stent placement are used. A randomized clinical trial (AVID) of angiography-directed versus IVUS-directed coronary stent placement is in progress (with a second soon to begin enrollment). In this trial, ultrasound guidance has been shown to improve acute procedural results, providing larger lumen dimensions without an increase in complication rates. IVUS guidance, however does not appear to affect the incidence of stent thrombosis within 30 days in the present era of high-pressure balloon inflations and aggressive antiplatelet therapy. Results concerning the effect of ultrasound-guided therapy on long-term target lesion revascularization rates are pending. To date, IVUS imaging has greatly contributed to advancements in coronary stent placement techniques. The future of IVUS-guided coronary stent placement will, of course, depend on the results of several ongoing clinical trials.

Intravascular ultrasound identification of stent entrapment in vivo with in vitro confirmation.

OBJECTIVES: One potential complication of stenting is "stent jail" due to placement of a stent across a side branch, which may impede additional interventions. Another form of stent entrapment may occur if the guidewire is accidentally withdrawn and then unknowingly passes through a stent loop during reentry with subsequent high pressure expansion. The purpose of this study was to evaluate this form of stent entrapment in vitro by intravascular ultrasound (IVUS). METHODS: A guidewire was passed through the end or middle diamonds of Palmaz-Schatz and Palmaz stents or the middle of Gianturco-Roubin stents. A 3.5 mm balloon was inflated over the guidewire through the various side holes of the stents. RESULTS: IVUS images presented three distinct patterns depending on the type of stent and position of balloon entry: 1) external compression and loss of wall continuity in the Palmaz-Schatz and Palmaz stents, 2) displacement of the side diamond across the lumen, and 3) external compression of the Gianturco-Roubin stent. The first and second patterns but not the third one were associated with impairment of lumen access. CONCLUSIONS: Based upon this in vitro verification, IVUS imaging can be used to identify the presence of stent entrapment in vivo.

Variability in tissue characterization of atherosclerotic plaque by intravascular ultrasound: a comparison of four intravascular ultrasound systems.

Different intravascular ultrasound (IVUS) systems vary in their image presentation. The purpose of this study was to compare four IVUS systems in vitro to determine the accuracy of tissue characterization of atherosclerotic plaque compared with histology. Ninety-eight plaque segments from 23 formalin-fixed human iliac arteries were imaged in saline at room temperature with four different IVUS systems. To assess the accuracy of IVUS in describing plaque, three types of analysis were performed: (1) the ability to identify the presence and extent of lumen or plaque boundary; (2) sensitivity, specificity, and interobserver variability of IVUS in qualitatively identifying plaque components compared with histology; and (3) quantification of calcification. The synthetic aperture device had a lower sensitivity in identifying lumen and plaque boundaries (87%, 38% respectively) compared with other machines (96%-100%, 95%-100%). All three mechanically rotating systems had fair to good sensitivities for identifying calcification (57%-73%) or lipid filled areas (50%-83%). The sensitivity of discriminating fibrous tissue from fatty areas was low (39%-52%). The synthetic aperture system had a significantly lower sensitivity for identifying all three tissue types (4%-21%). There was significant interobserver variability (kappa value = 0.47-0.68) as well as machine to machine variability (kappa value = 0.52) for tissue characterization. Calcified areas were underestimated by System 1 (p < .05) and System 4 (p < .01) because of weaker echo reflections or poor image quality. There are significant differences in image representation among these four IVUS systems in the diagnosis of tissue components of complex atherosclerotic plaque. These variabilities should be considered when interpreting studies performed with different machines.

Variability of a three-layered appearance in intravascular ultrasound coronary images: a comparison of morphometric measurements with four intravascular ultrasound systems.

The purpose of the study was to compare four intravascular ultrasound (IVUS) machines in vitro for their image representation of coronary arterial walls. There has been considerable variability among reported studies on the accuracy of morphometric measurements of coronary arteries by IVUS. This variability may be caused in part by the difference in the IVUS system used. A total of 24 formalin-fixed coronary arteries were imaged in saline at 37 degrees with four different IVUS systems. The images were interpreted independently and compared with histology. Each system had benefits and limitations: System 1 overestimated the lumen area and had difficulty in identifying the media; System 2 underestimated the media area, but had a lower positive bias for lumen area; System 3 overestimated the lumen area but more clearly identified tissue characteristics such as internal elastic membrane and the echolucent media zone which improved the likelihood of observing a three-layer appearance; and System 4 showed less distinct separation of the arterial components and had poor correlations with histology for media measurements. The ability to make accurate morphometric measurements from IVUS images depends on the clarity of the separation of plaque and media. Among the four systems studied, there is significant variability in the appearance of the ultrasound images and the accuracy of morphometric measurements. These system differences should be considered when comparing IVUS studies performed by different groups.

Distortion of intravascular ultrasound images because of nonuniform angular velocity of mechanical-type transducers.

The purpose of this study was to quantify nonuniform rotation in a current mechanical intravascular ultrasound (IVUS) instrument and its effect on arc, area, and diameter measurements. The accurate reconstruction of IVUS two-dimensional images is dependent on uniform rotation of the catheter tip. Prior investigations suggested that bends in the catheter driveshaft may be responsible for poor torque transmission, nonuniform rotation, and consequent errors in IVUS measurements. Eight 30 MHz mechanically driven IVUS catheters were evaluated in a model simulating the catheter course through the aorta and coronary ostium in a clinical study. Angular velocity and posi-ion profiles of the transducer, image angle, and diameter and area measurement errors were obtained from each catheter by imaging a vascular phantom with eight equispaced echogenic markers from concentric and eccentric positions. Six catheters also were tested for comparison in a simple curvature model. Rotational error was found in all catheters tested and worsened in the aortic model. Maximal angular error, defined as the largest angle between actual and presumed transducer direction, increased when measured in the aortic model as compared with the simple curvature model (17 +/- 12 degrees to 45 +/- 25 degrees; p < 0.05). Angles of 45 degrees were misrepresented with a mean range of values of 26 to 63 degrees. With eccentric catheter placement, area and diameters had average maximal absolute errors of 26% +/- 7.8% and 23% +/- 10%, respectively. In conclusion, nonuniform rotation of mechanical IVUS transducers constitutes a significant potential source of error in IVUS measurement of arcs of calcification, and lumen shape, area, and diameter.

Atheroma morphology and distribution in proximal left anterior descending coronary artery: in vivo observations.

OBJECTIVES: This study sought to examine, in vivo, the shape and position of atheroma in the proximal left anterior descending coronary artery. BACKGROUND: The prevalence, shape and location of atheromas involving the proximal left anterior descending artery have implications regarding the role of disturbed shear forces in the genesis of atherosclerosis. However, no data are available regarding in vivo findings or advanced disease. METHODS: Forty-two consecutive high quality intravascular ultrasound images were examined from patients with atherosclerotic disease in the proximal left anterior descending artery just distal to the left main bifurcation. Lesion percent area stenosis and maximal, minimal and flow divider intimal-medial thickness were measured at the region immediately after the circumflex takeoff. The angle formed by the midpoint of the flow divider, the human center of gravity and the maximal plaque thickness were determined. RESULTS: Eccentricity of vessel wall atheroma was observed such that the maximal wall thickness (1.42 +/- 0.50 mm [mean +/- SD]) differed significantly from minimal wall thickness (0.17 +/- 0.098 mm). Further, the region of vessel wall manifesting maximal thickness was greater than the flow divider thickness (0.26 +/- 0.16 mm). Maximal plaque thickness spared the region of the flow divider in 100% of cases and was positioned at a mean angle of 193 +/- 49 degrees from the center of the flow divider. Eccentric morphology was maintained across the 24% to 80% range of area stenosis. CONCLUSIONS: Atheromas in the very proximal left anterior descending artery are located opposite the circumflex takeoff, spare the flow divider and maintain eccentricity across a wide range of vessel stenoses. These in vivo morphologic data support the potential role of fluid dynamic mechanical factors in atherogenesis and have implications regarding the success of catheter-based interventional procedures at the site.

Intravascular ultrasound appearance of normal and mildly diseased coronary arteries: correlation with histologic specimens.

Intravascular ultrasound imaging was performed in vitro on six histologically normal and 104 minimally diseased arteries in patients aged 13 to 83 years. This study tested the hypothesis that normal coronary arteries produce a three-layer image that corresponds to the histologic layers of intima, media, and adventitia. The results showed a very good correlation between area of the echolucent ultrasound layer with the media and the inner echogenic layer with intimal area. In addition, a three-layer appearance was consistently seen when the internal elastic membrane was present with or without intimal hyperplasia. If the internal elastic membrane was absent, a three-layer appearance was still seen if the collagen content of the media was low. However, a two-layer appearance was observed when there was absence of the internal elastic membrane as well as a high collagen content of the media.

Three-dimensional reconstructions of the developing forebrain in rat embryos.

Using a computerized three-dimensional reconstruction technique with serially sectioned rat embryos, changes in the size and form of the forebrain were studied on Embryonic Days (E) 12 (1 day after closure of the neural tube), E15, E18, and E21 (2 days before birth). During this time, the forebrain changes from a relatively simple tubular structure with thin walls surrounding a large ventricular system to a thick-walled brain with a highly convoluted but reduced ventricular system. On E12, the two components of the forebrain, the telencephalon and the diencephalon, cannot be distinguished. Considering the forebrain as a whole (the embryonic prosencephalon), its volume continually increases between E12 and E21 due to the generation, differentiation, and maturation of neurons and glia. Attention was paid to changes in the sizes of the ventricles, the neuroepithelium and the parenchyma. Volumes of the ventricles and the surrounding neuroepithelium rapidly expanded from E12 to E18 and then decreased by E21, while the volume of the parenchyma continually increased. Differential growth of the telencephalon and that of the diencephalon were compared between E15 and E21. The expansion of the telencephalon was much larger than that of the diencephalon. In the telencephalon, the volumes of the lateral ventricles and the surrounding neuroepithelium increased between E15 and E18 and decreased by E21, while in the diencephalon the volumes of the third ventricle and its surrounding neuroepithelium continually declined between E15 and E21. That observation is compatible with previous work showing that the majority of diencephalic structures develop earlier than those in the telencephalon. It is important to note that volume changes in the ventricles and the neuroepithelium are maintained in "lock-step," suggesting a close relationship between the size of the ventricle and the size of the neuroepithelium.

Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.

A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.