Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

BACKGROUND: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters. METHODS: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. RESULTS: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL. CONCLUSIONS: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.

Is noninvasive determination of pulmonary artery pressure feasible using deceleration phase Doppler flow velocity characteristics in mechanically ventilated children with congenital heart disease?

Noninvasive determination of pulmonary hemodynamics is important for the management of congenital heart disease complicated by pulmonary hypertension. Flow deceleration is less influenced by right ventricular function and would allow more accurate estimation of pulmonary hemodynamics than acceleration. Respiratory influences on pulmonary blood flow are exaggerated by mechanical ventilation. Doppler-derived pulmonary artery (PA) blood flow velocity characteristics were therefore compared with pulmonary hemodynamic parameters in 42 mechanically ventilated children, aged 0.2 to 14.8 years (mean +/- SD 6.7 +/- 4.9). Mean PA pressure ranged from 11 to 47 mm Hg (21 +/- 9 mm Hg). Pulmonary hypertension was present in 14 patients. Significant differences were found between patients with and without pulmonary hypertension in maximal velocity (1.03 +/- 0.22 vs 0.88 +/- 0.18 m/s), acceleration time (119 +/- 39 vs 136 +/- 29 ms), maximal acceleration (17.6 +/- 6.4 vs 13.1 +/- 4.0 m/s2), mean acceleration (9.3 +/- 2.6 vs 6.7 +/- 2.0 m/s2), and mean deceleration (4.5 +/- 1.0 vs 3.8 +/- 0.8 m/s2). In contrast to our hypothesis of the deceleration phase-derived parameters, only maximal deceleration correlated with PA pressure. Acceleration parameters showed closer relations with PA pressures, but correlations were generally low and did not permit accurate prediction of PA pressure (SEE 5 to 11 mm Hg), PA resistance (SEE 1.14 U. m2) or PA driving force (SEE 7 mm Hg). An analysis that took respiratory phase into account did not improve correlations. Measurement of mean acceleration, maximal deceleration, and rate-corrected preejection period permitted for accurate discrimination between the presence or absence of pulmonary hypertension, with positive and negative predictive values being 92% and 90%. In mechanically ventilated children with congenital heart disease, accurate noninvasive PA pressure assessment is not possible. Accurate predictions for the presence of pulmonary hypertension can be made by measurement of both acceleration and deceleration parameters.

Limits of reproducibility of mitral pulsed Doppler spectra.

The total intrinsic variability of pulsed Doppler spectra of mitral blood flow was evaluated in this study. Doppler examinations were performed in 10 normal volunteers (7 men, 3 women), ages 29 to 57 years (mean 41) with an interval period of 3 months. The recordings were made in the apical 4-chamber view, using a 2.25-MHz transducer. The sample was placed approximately 1 cm proximal (left atrium) and 1 cm distal (left ventricle) from the middle of the anulus of the mitral valve at the onset of diastole. Processing of the raw Doppler spectra was done in a way that avoided subjective manipulation by the investigators. Mitral peak velocities, accelerations and spectral widths were measured in early diastole and late diastole. From the parameters under investigation, maximal velocities showed the best reproducibility with a range of coefficients of variation of 9 to 13%. Peak acceleration in early diastole and spectral widths showed rather large coefficients of variation, ranging from 19 to 30 and 14 to 24%, respectively. Mitral pulsed Doppler spectra in the left atrium were more reproducible than in the left ventricle.

MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome.

Bilateral microphthalmia with blepharophimosis, linear lesions of dermal aplasia involving the face, and microcephaly were present in a newborn girl who died at age 9 months from cardiomyopathy resulting in ventricular fibrillation. Autopsy showed an atrial septum defect, persistent gross trabeculation of the left ventricle, and an arteria lusoria. This case represents a further example of a new entity for which we propose the term MIDAS syndrome. The acronym stands for microphthalmia, dermal aplasia, and sclerocornea. Our patient is the second with this syndrome to have a major congenital heart defect. Cytogenetic studies reported in previous cases indicate that the underlying gene defect can be assigned to Xp22.3. This new X-linked male-lethal trait should be distinguished from focal dermal hypoplasia that will be found to map elsewhere on the X-chromosome.

Hypoplastic aortic arch with aortic coarctation: surgical correction.

This report describes an alternative operation for hypoplastic aortic arch. The technique conserves the vascularization of the left arm and avoids the need of using flaps or free patches. The operative procedure is documented in three patients.

A comparison of coarctation resection and subclavian flap angioplasty using ultrasonographically monitored postocclusive reactive hyperemia.

The reported relatively high incidence of early restenosis at the coarctation repair site with subclavian flap angioplasty, especially in infants less than 3 months of age, prompted a physiologically oriented analysis of relief of obstruction from coarctation after subclavian flap angioplasty versus resection and end-to-end anastomosis in infancy. Twenty-one patients who had undergone repair of coarctation in infancy by either subclavian flap angioplasty (nine patients) (median age 8 years) or resection and end-to-end anastomosis (12 patients) (median age 8 years) were evaluated by Doppler spectrum analysis of the blood flow velocities in the femoral artery at rest and during reactive hyperemia. The median resting right upper to lower limb systolic pressure difference (with interquartile range) was similar in the angioplasty, resection and anastomosis, and control groups: -5 mm Hg (18 mm Hg), 0 mm Hg (12 mm Hg), and -2.5 mm Hg (10 mm Hg), respectively. Also, similar resting values for the maximum frequency of the advancing curve and the pulsatility and resistance indices were measured in the three groups. During reactive hyperemia of the leg, however, a significant hemodynamic obstruction across the repair site became clinically manifest in the angioplasty group only, as documented by a lower pulsatility index in comparison with the control group (p = 0.01, Mann-Whitney U test). Comparison of the hemodynamic results between the angioplasty and resection and anastomosis groups in subdivisions of infants operated on at an age of less or greater than 3 months, both at rest and during reactive hyperemia, showed, already at rest, a significantly lower value for the pulsatility index in the former angioplasty subdivision (p = 0.05, Student's t test), indicating a significant resistance at the coarctation repair site in the angioplasty patients operated on before the third month of life. A disadvantage of angioplasty (compared with resection and anastomosis) was noted when angioplasty was performed before the third month of life, and an unequivocal lack of advantage was noted when performed beyond that period regarding relief of obstruction from coarctation. In addition, a definite potential for adverse long-term effects on the hemodynamics of the left upper limb after subclavian flap angioplasty in infancy has been documented. For these reasons we prefer to perform resection and end-to-end anastomosis for repair of coarctation in infancy.

Appraisal of resection and end-to-end anastomosis for repair of coarctation of the aorta in infancy: preference for resection.

Between 1973 and 1987, 70 consecutive infants under-went repair of coarctation of the aorta. Age at operation was 80.0 +/- 77 days (mean +/- standard deviation); mean weight was 3.0 +/- 0.5 kg. Isolated coarctation was present in 25 patients (group 1); in 19 patients coarctation existed in association with ventricular septal defect (group 2); and in 26 patients coarctation was associated with major intracardiac defects (group 3). Subclavian flap angioplasty was performed in 19 patients and resection and end-to-end anastomosis in 51 patients. Hospital mortality was not significantly different between subclavian flap angioplasty (11%) and resection and end-to-end anastomosis (24%). Freedom from reintervention for recoarctation after 5 years was 87% in the subclavian flap angioplasty group and 95% in the group having resection and end-to-end anastomosis. Actuarial survival at 5 years was 100% for group 1, 73% for group 2, and 28% for group 3. In the subclavian flap angioplasty group, we observed detrimental effects of the sacrifice of the left subclavian artery: 1 patient had a 2.5-cm shortening of the left upper arm, and 5 others complained of claudication in the left upper limb during strenuous exercise. As no major advantage in terms of mortality and recoarctation to either technique of coarctation repair was found, and as subclavian flap angioplasty carries the possible disadvantage of late contracture of isthmic ductal tissue and possible detrimental effects on the left upper limb, resection and end-to-end anastomosis is recommended.

Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines.

This study investigated improvement of diagnosing myocardial damage caused by anthracyclines using tissue Doppler imaging (TDI). The optimal set of conventional echocardiographic and/or TDI parameters, needed for the discrimination of survivors from healthy controls, was retrospectively assessed. A total of 60 patients and 99 controls, age range 8.5 to 17.6 years, were studied. The survivors received 50 to 400 mg/m(2) cumulative dose of anthracyclines, with a mean follow-up of 7.3 (+/-2.3) years. The parameters used in the discriminant score (S-score) were selected from a large set of 51 echocardiographic parameters, using logistic regression analysis (stepwise selection). The correct classification probability (C-index) and the generalized distance (d) between the distributions of S-scores were used to measure the overall discriminative performance of each echocardiographic technique separately and in combination. The overall discriminative performance of the conventional echo-Doppler parameters (C = 77.3%, d = 1.04) was lower than that of the TDI (C = 84.2%, d = 1.37); the highest C-index was obtained using both techniques (C = 89.2%, d = 1.66). The set of parameters includes: LV fractional shortening and MV early diastolic flow velocity, two long-axis and five apical 4-CV TDI wall velocities (systolic and diastolic). In the patient group, the S-score was positively associated with cumulative dose of anthracyclines (p = 0.05) and duration of treatment (p = 0.01). The diagnostic index S-score, based on a limited number of variables from both techniques simultaneously, could retrospectively discriminate asymptomatic children with anthracycline-induced cardiomyopathy from healthy controls. The potentials of the S-score for serial and prospective studies are further investigated.

Assessment of myocardial velocities in healthy children using tissue Doppler imaging.

The objective was to determine the normal range of tissue velocities in paediatric hearts as measured by tissue Doppler imaging. A prospective study was carried out involving 160 healthy children (mean age 10.8 y, range 4.0-17.9 y). Using tissue Doppler imaging (TDI) from parasternal long axis and apical views, peak velocities and peak myocardial velocity differences across the right ventricular anterior wall, interventricular septum and left ventricular posterior wall were assessed during systole, early and late diastole. The existence of transmyocardial velocity differences between the left and right side of the interventricular septum, as well as between the endocardium and epicardium of the left ventricular posterior wall was observed throughout the heart cycle. With range-gated TDI from apical four-chamber view, peak velocities were measured within the basal, mid and apical parts of the interventricular septum, and the left and right free ventricular walls. The highest peak systolic, early and late diastolic velocities were measured within the basal parts of all myocardial walls. The ranges of the calculated velocity ratios (early-to-late diastolic velocity and early diastolic-to-systolic velocity) for the various wall parts appeared to be overlapping. The correlations of peak myocardial tissue velocities and their ratios with age and weight were weak and practically irrelevant. These normal values of peak myocardial velocities, transmyocardial velocity differences and the ratios of peak wall velocities can be used as reference values in future investigations of ventricular dysfunction in this age group.

Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines.

The applicability of tissue Doppler imaging (TDI) was investigated for estimating cardiac function in long-term survivors of childhood cancer treated with anthracyclines. A total of 63 children (age range 7.8-17.3 y) underwent standard echo Doppler cardiographic studies of blood flow velocities, left ventricular dimensions and fractional shortening, followed by measurements of peak myocardial velocities and direction using the noninvasive tissue Doppler imaging (TDI) technique. All 63 were late survivors (median 7.1 y, range 3.5-13.5 y after end of therapy) who had received mean (+/- SD) cumulative dose of 242 (+/- 141) mg/m(2) of anthracyclines. The control group consisted of 160 healthy subjects (age range 4 to 17.9 y). Standard echo-Doppler anatomical parameters that were found significantly (p < 0.01) different for the study group are: RV wall thickness (decreased); LV diameter (increased); and LV fractional shortening (decreased). Studied hemodynamic parameters were not found to be different between the two groups. Quantitative TDI parameters: peak late diastolic myocardial velocities, as well as transmyocardial systolic and diastolic velocity differences, were significantly lower in late survivors than in the healthy pediatric population (p < 0.01). Qualitative local functional impairment of the movement of the left ventricular walls was detected in 20% of the patients. TDI might become a useful noninvasive method for detecting subclinical myocardial damage in apparently healthy children who received moderate doses of anthracyclines for treatment of childhood malignancy. Prospective studies with TDI for the detection of regional myocardial abnormalities are recommended.

Repeatability of Doppler ultrasound measurement of blood flow velocity and its variability in the supraclinoid segment of the internal carotid artery in preterm newborns.

Accuracy of transfontanellar Doppler ultrasound measurement of blood flow velocity and its variability in the supraclinoid segment of the internal carotid artery was studied in preterm newborns. Measurements were performed in duplicate, on a well defined site, under negligible angle of insonation, and during stable physical condition. The measurements included the base value and variability over 20 seconds, for: diastolic velocity; mean velocity; systolic velocity; resistance index; diastolic time interval; systolic time interval; heart beat duration. As a measure of accuracy the coefficient of repeatability was calculated for each parameter. Coefficients several times smaller than the range of measured values, were found for most parameters. These parameters and their coefficients include: diastolic velocity (base value 3.1 cm s-1, variability 1.6 cm s-1); mean velocity base value 3.1 cm s-1; systolic velocity base value 4.5 cm s-1; resistance index (base value 0.13, variability 0.08); diastolic time interval base value 25 ms; systolic time interval base value 27 ms; heart beat duration base value 27 ms. Thus, Doppler ultrasound enables differentiation within the biological variation of certain properties of cerebral blood flow.

Automated calculation of stenosis diameters from the width of the velocity jet with the use of a multi-gate pulsed Doppler system.

The aim of this study was to evaluate an algorithm for automated estimation of the width of a jet stream originating from a stenosis. The evaluation was performed in a pulsatile flow model. The width of the jetstream was assessed by measuring the diameter of the region with relatively high velocities (the jet) in the velocity profiles, as recorded with a multi-gate pulsed Doppler system. Measurements were performed at 3, 6, and 9 mm downstream of three different stenoses (stenosis diameter: 3, 5, or 8 mm) at different Reynolds numbers (200-1600) based on time averaged flow velocity for a tube of diameter 15 mm. The developed algorithm was used successfully for automated detection and quantification of jet flow diameters downstream to a stenosis. The algorithm can be used for calculating the stenosis diameter notwithstanding a theoretically predictable overestimation of about 1 mm, depending on the Reynolds number and the distance from the stenosis.

Cerebral blood flow velocity and pulsation in neonatal respiratory distress syndrome and periventricular hemorrhage.

The present study addressed the hypotheses that cerebral ischemia and/or excessive cerebral blood pulsation contribute to periventricular hemorrhage in preterm newborns with respiratory distress and that the pulse width is a valuable tool to estimate the contribution of cerebral blood pulsation. These hypotheses were tested by following preterm newborns at risk for respiratory distress and periventricular hemorrhage. We monitored for cerebral blood flow velocity (CBFV), cerebral pulse width, and cerebral pulsatility index; for patent ductus arteriosus, capillary Pco2, heart rate (HR) and behavior; and for the occurrence of respiratory distress and periventricular hemorrhage (PVH). The data obtained were analyzed with linear regression with the mode of respiration (spontaneous or supported) and postnatal age as additional covariates. We observed that (a) respiratory distress, either uncomplicated or complicated by PVH, correlates with a low CBFV and a high cerebral pulsatility index; (b) PVH also correlates with a high cerebral pulse width; (c) the increased pulse width precedes the onset of the hemorrhage; and (d) these CBF alterations can be partly attributed to ductal shunting and are ameliorated by mechanical ventilation.

Asymmetry of the cerebral blood flow: an ultrasound Doppler study in preterm newborns.

The purpose of this study was to investigate whether the preference of periventricular hemorrhage (PVH) for the left hemisphere is due to asymmetry of cerebral blood flow (CBF) and, if so, whether this asymmetry is due to patent ductus arteriosus (PDA). Thirty-three preterm newborns at risk for PVH were followed during their first 5 days after birth. Internal carotid CBF velocity (CBFV) and the flow direction in the common pulmonary artery, both determined by ultrasound Doppler, served as measures of CBF and PDA, respectively. The difference between right and left CBFV was analyzed statistically, with outcome, PDA, capillary PCO2, behavior, heart rate, and the average of right and left CBFV as covariates. Infants who developed PVH (n = 7) exhibited CBFV asymmetry to the disadvantage of the left side. This finding was partially attributable to PDA. Without PVH there was no significant CBFV asymmetry. Because all hemorrhages were bilateral, a relationship with the side of the hemorrhage could not be explored. In conclusion, asymmetry of CBFV is not normal, but is associated with PVH and PDA.

Influence of end expiratory pressure on cerebral blood flow in preterm infants.

The effect of interruption of positive and expiratory pressure (PEEP) on cerebral blood flow velocity (CBFV) and CBF fluctuation (CBFF) in the internal carotid arteries and on heart rate, restlessness and wakefulness has been studied in 17 mechanically ventilated neonates with RDS. A decrease in CBFV was found, but no significant change in CBFF. Multiple regression analysis showed that the decrease in CBFV is less pronounced if the PEEP interruption is accompanied by restlessness. It further appeared that the decrease in CBFV is more pronounced if CBFV is high, the ductus arteriosus is patent, or RDS follows a complicated course. These findings indicate that PEEP supports CBF, probably by a decrease in ductal stealing from the brain. Therewith PEEP protects against cerebral hypoperfusion which is one of the major risks in RDS and immaturity. Furthermore, our findings suggest that the decrease in CBF during PEEP interruption is moderated by restlessness and accentuated by brain damage.

Cerebral blood flow fluctuation in neonatal respiratory distress and periventricular haemorrhage.

The relationship of cerebral blood flow fluctuation (CBFF) with periventricular haemorrhage (PVH) and respiratory distress syndrome (RDS) was studied in 35 preterm newborns. CBFF was defined as the interquartile range in the ensemble of pulses of a 20-s Doppler recording of CBF velocity (CBFV) in the internal carotid artery. We found a statistically significant increase in end diastolic CBFF in PVH and RDS. This increase was related to the mode of respiration (spontaneous or mechanically supported), the state of the ductus arteriosus, and the level of end diastolic CBFV. Differences before and after the onset of PVH were not found. In view of this, we conclude that RDS increases CBFF, that this increase is related to pleural pressure fluctuations, that these can be damped by mechanical ventilation, and that their propagation to the CBF is promoted by patency of the ductus arteriosus and foramen ovale. Whether the CBFF increase causes PVH, or is merely an expression of coincident RDS, remains a question that needs further investigation.

Diagnostic ultrasound equipment. Safety and dosimetry.

A survey of present opinions on the safety of diagnostic ultrasound applications is presented together with some data on output levels. Physical mechanisms involved in potential adverse effects are described. Labelling requirements of the equipment are defined and specified. These requirements are contained in a recent proposal of the Netherlands' Committee on the Safety of Ultrasound.

Cerebral blood flow fluctuation in low-risk preterm newborns.

Cerebral blood flow (CBF) fluctuation was studied by analyzing Doppler internal carotid blood velocity recordings of 13 healthy preterm newborns obtained in the course of their first 5 days of life. As measures of fluctuation we used the interquartile range (IQR) and the coefficient of variation (CV) of the ensemble of heart beats of a 20-s recording. In this way we determined fluctuation of the following velocity curve parameters (VCPs): end diastolic velocity; mean velocity; peak systolic velocity and pulsatility index (PI). The pooled data 5-95% intervals for fluctuation thus measured, were: 93-281% for CV; 0.6-3.7 cm/s for the IQR of the velocities; and 4-19% for the PI-IQR. Multiple regression analysis of IQR revealed significant relationships with: the VCP level; with restlessness; and with patency of the ductus arteriosus. Our findings imply that: (1) CBF has various qualities with different stability, mean velocity being the most stable; (2) for all the VCPs investigated, fluctuation is physiological in the early days after preterm birth; (3) most likely, there exists no age trend; (4) restlessness rather than wakefulness, enhances fluctuation; (5) patent ductus arteriosus destabilizes CBF; and (6) for a proper insight into fluctuation, the level of the VCP in question must be taken into account. We suggest that, the enhancing effect that patent ductus arteriosus has on fluctuation pays a contribution to the pathogenesis of brain damage. Finally, we conclude that the IQR represents fluctuation better than does the more commonly used CV.

A denaturated venous homograft as an alternative material for shunts and other reconstructions in congenital cardiac surgery.

A human venous homograft "Varivas R", in clinical use for 10 years for vascular access loops and femoropopliteal bypasses, has been used since December 1985 as a material for aortopulmonary shunts and other reconstructive procedures in congenital heart surgery. For this purpose vein segments 5 cm length, varying in diameter from 4 up to 10 mm by steps of 1 mm, were obtained. Our experience with Varivas is limited to 59 patients. Of 47 infants, 18 received a left, and 25 a right sided aortopulmonary shunt, 9 had bilateral aortopulmonary shunts, 2 right ventricle pulmonary conduits, 1 a pulmonary-pulmonary conduit, 3 interrupted aortic arch reconstructions and 4 a central aortopulmonary shunt, 1 with confluence reconstruction, 3 recidives of coarctation a patch repair. Among 11 adults 6 received coronary bypass and 6 others vascular reconstructions. In contrast to other artificial graft materials, the vein material offers easy manipulation similar to the daily routine of handling fresh vein material offers easy manipulation similar to the daily routine of handling fresh vein grafts in coronary surgery. The appropriate diameter sizes match better the infants anatomy, without the risk of kinking and/or anastomosis displacement. Peroperatively it was possible to confirm patency by electromagnetic flow measurement and the postoperative examinations were done by colour Doppler echocardiography. We had to reoperate upon 4 infants because of early thrombosis; on 1 infant for stenosis of the graft and on another 5 for late thrombosis. In an attempt to extend the indications for "inoperable" pulmonary hypoplasia/atresia we were not able to keep the shunt open in 4 infants.

Thrombus detection on central venous catheters in the neonatal intensive care unit.

Between September, 1989, and September, 1992, 193 infants were investigated prospectively for development of central-venous-catheter-induced thrombosis. In 25 infants intracardiac or central-venous-catheter-induced thrombosis was demonstrated (13%). A slightly higher incidence of thrombosis was found in infants with umbilical catheters in comparison with infants with subclavian catheters, although no significant difference was demonstrated. The results make clear that central venous catheters in neonatal intensive care have considerable risk in developing central venous or intracardiac thrombosis, and echocardiography is an excellent technique for diagnosing these thromboses.